Pyrazolyl-substituted pyridone compounds as serine protease inhibitors

ABSTRACT

There are provided inter alia pyrazolyl-substituted pyridone compounds, which exhibit biological activity, e.g., inhibitory action, against serine proteases, including thrombin and various kallikreins. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which disease or disorder is amenable to treatment or prevention by the inhibition of serine proteases, including thrombin and various kallikreins.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Division of U.S. application Ser. No.15/512,037, filed Mar. 16, 2017, which is a U.S. National Stage entryunder 35 U.S.C. § 371 of International Application No.PCT/US2015/050809, filed on Sep. 17, 2015, designating the United Statesof America and published in English on Mar. 24, 2016, which in turnclaims priority to U.S. Provisional Application Nos. 62/051,511 and62/051,585, filed on Sep. 17, 2014, each of which is hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The invention disclosed herein generally relates topyrazolyl-substituted pyridine compounds, their use in treatingdisorders involving serine proteases, including thrombin and variouskallikreins, and methods of treating such disorders involving saidcompounds.

BACKGROUND

Serine proteases are a large family of enzymes with diverse biologicalfunctions, their commonality being the presence and critical function ofthe active-site serine residue. Their central function is the catalyticscission of peptide bond substrates via a Ser, His, Asp triad within theactive site (Kraut, J. Annual Review of Biochemistry 1977, 46, 331-358)

The present disclosure relates to compounds, e.g., pyrazolyl-substitutedpyridone compounds, which exhibit biological activity, e.g., inhibitoryaction, against serine proteases, including thrombin and variouskallikreins.

Kallikreins are a subgroup of serine proteases, divided into plasmakallikrein and tissue kallikreins. Plasma kallikrein (KLKB1) liberateskinins (bradykinin and kallidin) from the kininogens, peptidesresponsible for the regulation of blood pressure and activation ofinflammation. In the contact activation pathway of the coagulationcascade, plasma kallikrein assists in the conversion of factor XII tofactor XIIa (Keel, M.; Trentz, O. Injury 2005, 36, 691-709). Factor XIIaconverts factor XI into factor XIa, which in turn activates factor IX,which with its co-factor factor VIIIa forms the tenase complex, whichfinally activates factor X to factor Xa. In the fibrinolysis part of thecoagulation cascade, plasma kallikrein serves to convert plasminogen toplasmin. Thus, it has been proposed that plasma kallikrein inhibitorscan be useful in the treatment of thrombotic and fibrinolytic diseasesand disease conditions (U.S. Pat. No. 7,625,944; Bird et al. Thrombosisand Hemostasis 2012, 107, Dhaval Kolte, M D. et al., Cardiology inReview, 2015).

In rodent models, it has been shown that activation of plasma kallikreinin the eye increases retinal vascular permeability; whereas inhibitionof the kallikrein-kinin system reduces retinal leakage induced bydiabetes and hypertension. These findings suggest that intraocularactivation of the plasma kallikrein pathway can contribute to excessiveretinal vascular permeability that can lead to diabetic macular edema(DME). Thus, evidence suggests that plasma kallikrein inhibitors canprovide a new therapeutic opportunity to reduce retinal vascularpermeability (Feener, E. P. Curr Diab Rep 2010, 10, 270).

Hyperglycemic and diabetic individuals have an elevated risk ofhemorrhage during thrombolytic therapy. In rodent models ofintracerebral hemorrhage (ICH), it has been shown that KLKB1 inhibitionor knockout reduces this effect. While the mechanism is not fullyunderstood, this evidence suggests that plasma kallikrein inhibitors canbe useful in the treatment of cerebral hemorrhage (Feener, E. P. CurrDiab Rep 2010, 10, 270).

Plasma kallikrein and Factor XIIa inhibitors have been shown to beneuroprotective in animal models of acute ischemic stroke and traumaticbrain injury, reducing edema formation, inflammation, and thrombosis(Albert-Weißenberger C, Siren A L, Kleinschnitz C. Prog Neurobiol. 2013,101-102, 65-82). Thus, evidence suggests that plasma kallikreininhibitors can be useful in the treatment of acute ischemic stroke andtraumatic brain injury.

Plasma kallikrein can also cleave glucagon-like peptide 1 (GLP-1) andneuropeptide Y (NPY), both substrates for dipeptidyl peptidase-4(DPP-4), a validated diabetes drug target. In the case of GLP-1,cleavage by KLKB1 reduces both its potency as well as plasma stability.In the case of NPY, cleavage by KLKB1 reduces its affinity to the Y2 andY5 receptors. Thus, evidence suggests that plasma kallikrein inhibitorscan be useful in the modulation of energy homeostasis and in thetreatment of diabetes. (Feener, E. P. Curr Diab Rep 2010, 10, Feener, E.P. et al., Biol. Chem. 2013, 394, 319).

The Kallikrein-kinin system is involved in the regulation of vascularendothelial growth factor (VEGF), endothelial NO synthase, andfibroblast growth factor 2, all of which are involved in angiogenesis(Bader M. 2009, Arteriosclerosis, Thrombosis, and Vascular Biology, 29:617). Tissue kallikrein (KLK1) has been linked to blood vessel growth(Miura S., 2003, Hypertension, 41, 1118). Therapies that moderateangiogenesis have been proposed for the treatment of both diabeticmacular edema (DME) and age-related macular degeneration (AMD) (Syed, B.A.; Evans, J. B.; Bielory, L., 2012, Nature Reviews Drug Discovery, 11,827). Without further wishing to be bound by any theory, it is thereforereasonable to conclude that kallikrein inhibitors, including KLK1inhibitors, can be useful in the treatment of diabetic retinopathy, DME,and AMD.

Studies have shown that inflammation plays an important role in theorigin and development of AMD, and treatment often includesanti-inflammatories such as corticosteroid (Telander, D., 2011, Seminarsin Ophthalmology, 26(3), 192). The connection between thekallikrein-kinin system and inflammation is also well established(Duchene, 2011, “Kallikrein-kinin kystem in inflammatory diseases”.Kinins. De Gruyter. 261). Without further wishing to be bound by anytheory, it is reasonable to conclude that the anti-inflammatory natureof kallikrein (e.g. KLK1 and KLKB1) inhibitors can be useful in thetreatment of AMD.

Ecallantide (Kalbitor) is a 60-amino acid recombinant protein that actsas a potent reversible inhibitor of plasma kallikrein (Schneider L, etal., J Allergy Clin Immunol 2007, 120, 416). Ecallantide has beenapproved by the FDA for the treatment of acute attacks of hereditaryangioedema (HAE). Without further wishing to be bound by any theory, itis reasonable to believe that plasma kallikrein inhibition in generalcan be a useful treatment for HAE, and thus there is strong interest inthe development of plasma kallikrein inhibitors as a therapy for HAE.

Tissue kallikreins (KLKs, for example, KLK1) are subdivided into varioustypes, and have been extensively investigated in cancer and inflammationbiology. Various kallikrein KLKs have been found to be up- ordown-regulated in various cancer types, such as cervical-, testicular-,and non-small-cell lung adenocarcinoma (Caliendo et al. J. Med. Chem.,2012, 55, 6669). Furthermore, overexpression of various KLKs in the skinhas led to the recognition that certain kallikrein inhibitors can beuseful for certain dermatological conditions, including atopicdermatitis, psoriasis and rare skin diseases such as Netherton Syndrome(Freitas et al. Bioorganic & Medicinal Chemistry Letters 2012, 22,6072-6075). A thorough discussion of tissue kallikreins, plasmakallikrein, their functions and potential roles in various diseases canbe found in a variety of references, including the following which areincorporated herein by reference in their entireties and for allpurposes: Renné, T.; Gruber, A. Thromb Haemost 2012, 107, 1012-3;Sotiropoulou, G.; Pampalakis, G. Trends in Pharmacological Sciences2012, 33, 623-634; Pampalakis, G.; Sotiropoulou, G. Chapter 9Pharmacological Targeting of Human Tissue Kallikrein-Related Peptidases.In Proteinases as Drug Targets, Dunn, B., Ed. The Royal Society ofChemistry: 2012; pp 199-228; Caliendo, G.; Santagada, V.; Perissutti,E.; Severino, B.; Fiorino, F.; Frecentese, F.; Juliano, L. J Med Chem2012, 55, 6669-86.

Daiichi Seiyaku Co Ltd received approval in Japan to market cetraxatefor gastritis and peptic ulcers. Cetraxate is reported as a plasmakallikrein inhibitor (WIPO Patent Application WO/2006/108643). Withoutfurther wishing to be bound by any theory, it is reasonable to believethat plasma kallikrein inhibition in general can be useful in thetreatment of gastritis and peptic ulcers.

Thrombin (fIIa, the active form of prothrombin) is another serineprotease that is involved in the coagulation cascade. In mammaliansystems, blood vessel injuries result in bleeding events, which aredealt with by the blood coagulation cascade. The cascade includes theextrinsic and intrinsic pathways, involving the activation of at least13 interconnected factors and a variety of co-factors and otherregulatory proteins. Upon vascular injury, plasma factor VII interactswith exposed Tissue Factor (TF), and the resultant TF-fVIIa complexinitiates a complex series of events. Factor Xa is produced directly‘downstream’ from the TF-fVIIa complex, and amplified manifold via theintrinsic Pathway. FXa then serves as the catalyst for formation ofthrombin (fIIa), which in turn is the direct precursor to fibrinolysis.The outcome is a fibrinolytic clot, which stops the bleeding.Fibrinolysis of the polymeric clot into fibrin monomers leads todissolution and a return of the system to the pre-clot state. Thecascade is a complex balance of factors and co-factors and is tightlyregulated. In disease states, undesired up- or down-regulation of anyfactor leads to conditions such as bleeding or thrombosis.

Historically, anticoagulants have been used in patients at risk ofsuffering from thrombotic complications, such as angina, stroke andheart attack. Warfarin has enjoyed dominance as a first-in-lineanticoagulant therapeutic. Developed in the 1940s, it is a Vitamin Kantagonist and inhibits factors II, VII, IX and X, amongst others. It isadministered orally, but its ease of use is tempered by other effects:it has a very long half-life (>2 days) and has serious drug-druginteractions. Importantly, since Vitamin K is a ubiquitous cofactorwithin the coagulation cascade, antagonism results in the simultaneousinhibition of many clotting factors and thus can lead to significantbleeding complications.

Much attention has been focused on heparin, the naturally-occurringpolysaccharide that activates AT III, the endogenous inhibitor of manyof the factors in the coagulation cascade. The need for parenteraladministration for the heparin-derived therapeutics, and theinconvenient requirements for close supervision for the orally availablewarfarin, has resulted in a drive to discover and develop orallyavailable drugs with wide therapeutic windows for safety and efficacy.Indeed, the position of thrombin in the coagulation cascade has made ita popular target for drug discovery. Without wishing to be bound by anytheory, it is believed that the ultimate development of direct thrombininhibitors (DTIs) is usefully based upon the classical D-Phe-Pro-Argmotif, a sequence that mimics fibrinogen, which is a natural substrateof thrombin. Without further wishing to be bound by any theory, it isbelieved that the use of DTIs is very well precedented, such as with thehirudin-based anticoagulants, and thus there is strong interest in thediscovery and development of novel DTIs.

A thorough discussion of thrombin and its roles in the coagulationprocess can be found in a variety of references, including the followingwhich are incorporated herein by reference in their entireties and forall purposes: Wieland, H. A., et al., 2003, Curr Opin Investig Drugs,4:264-71; Gross, P. L. & Weitz, J. I., 2008, Arterioscler Thromb VascBiol, 28:380-6; Hirsh, J., et al., 2005, Blood, 105:453-63; Prezelj, A.,et al., 2007, Curr Pharm Des, 13:287-312.

It will be obvious to one who is skilled in the art that plasma andtissue kallikreins and thrombin are only a few of the many serineproteases that are relevant to the treatment or prevention of certaindisorders or diseases

SUMMARY OF THE INVENTION

Embodiments of the present invention encompass compounds including asubstituted or unsubstituted pyridone ring attached to a substituted orunsubstituted pyrazole ring with structure of Formula (I):

or pharmaceutically acceptable salts, esters, solvates, or prodrugsthereof, wherein L¹ can be a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, —S—, —O—, or—NR⁶—; L² and L⁴ are independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, or—SO₂—; L³ and L⁵ are independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, or —O—; R¹ can behydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl; R² and R⁴ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl; R³ and R⁵ areindependently hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; and R⁶ can behydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; provided that if the compound has a structure according toFormula (IIa), as follows, either L³ is not a bond or R³ is nothydrogen:

In some embodiments, the compound can have the structure of Formula(IIa), Formula (IIIa), Formula (IVa), or Formula (Va):

In some embodiments, L² can be a bond, and R² can be hydrogen.

In some embodiments, the compound can have the structure according toany of Formula (IIIa), Formula (IVa), or Formula (Va) as set forthabove, wherein L³ can be a bond, and R³ can be hydrogen.

In some embodiments, L⁴ can be a bond and R⁴ can be hydrogen. In someembodiments, L⁵ can be a bond, and R⁵ can be hydrogen.

In some embodiments, L² can be —C(O)—, and R² can be substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl. In some embodiments, R² can be substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In someembodiments, the aryl or heteroaryl can be phenyl, 2-chlorophenyl,2-methoxyphenyl, phenyl-3-carboxylic acid, phenyl-3-carboxamide,3-(hydroxymethyl)phenyl, phenyl-4-carboxylic acid, phenyl-4-carboxamide,4-(hydroxymethyl)phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,3-oxazol-2-yl,1,3-oxazol-4-yl, or 1,3-oxazol-5-yl. In some embodiments, R² can besubstituted or unsubstituted alkyl. In some embodiments, R² can betert-butyl, 1,1-dimethyl-2-hydroxy-ethyl, 1,1-dimethyl-2-methoxy-ethyl,or 1,1-dimethyl-2-cyclopropoxy-ethyl.

In some embodiments, L¹ can be bond, —S—, —O—, —NR⁶—, substituted orunsubstituted alkylene, or substituted or unsubstituted heteroalkylene,and R¹ can be hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted aryl, substituted or unsubstituted fused ring aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments, the aryl or heteroaryl can bephenyl, 4-fluorophenyl, 4-chlorophenyl, 2-thienyl, or5-chloro-thien-2-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl,2-chloro-1,3-thiazol-5-yl, or 5-chloro-1,3-thiazol-2-yl.

In some embodiments, L⁴ can be a bond or substituted or unsubstitutedalkylene, and R⁴ can be substituted or unsubstituted aryl, substitutedor unsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl. In some embodiments, the heteroaryl can be pyridyl,pyridazinyl, pyrimidinyl, thienyl, or furyl. In some embodiments, L⁴ canbe substituted or unsubstituted alkylene, and R⁴ can be substituted orunsubstituted heterocycloalkyl. In some embodiments, theheterocycloalkyl can be morpholinyl, oxanyl, or oxetanyl. In someembodiments, L⁴ can be a bond, and R⁴ can be substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl

In some embodiments, L³ can be bond, and R³ can be halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In some embodiments, the aryl or heteroaryl can be phenyl,pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. In someembodiments, the alkyl or heteroalkyl can be methyl or cyano.

In some embodiments, L⁵ can be bond, and R⁵ can be hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

In some embodiments, the compound can be selected from any compoundlisted in Table A. In some embodiments, the compound can be selectedfrom any compound listed in Table B (Appendix A).

Embodiments of the present invention also relate to pharmaceuticalcompositions including a compound as described above, and apharmaceutically acceptable excipient.

Embodiments of the present invention also encompass methods for treatinga disease or disorder in a subject, including administering a compoundor a pharmaceutical composition as described above, to a subject in needthereof in an amount effective to treat or prevent the disease ordisorder.

In some embodiments, the disease or disorder can be a thromboticdisorder or a kallikrein-related disorder.

In some embodiments, the thrombotic disorder can be acute coronarysyndrome, venous thromboembolism, arterial thromboembolism, cardiogenicthromboembolism, disseminated intravascular coagulation, or a blood clotthrombus. In some embodiments, the compound acts by inhibiting thrombin.

In some embodiments, the kallikrein-related disorder can be a thromboticdisease, a fibrinolytic disease, a type of cancer, an inflammatorycondition, a dermatological condition, or an ophthalmic disease. In someembodiments, the ophthalmic disease can be diabetic macular edema,age-related macular degeneration, or diabetic retinopathy. In someembodiments, the type of cancer can be cervical-, testicular-, ornon-small-cell lung adenocarcinoma. In some embodiments, theinflammatory condition can be sepsis, inflammatory bowel disease,systemic inflammatory response syndrome, or rheumatoid arthritis. Insome embodiments, the compound acts by inhibiting plasma kallikrein. Insome embodiments, the compound acts by inhibiting tissue kallikrein.

In some embodiments, the disease or disorder can be fibrosis,Alzheimer's Disease, multiple sclerosis, pain, or cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

Not applicable.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless otherwise noted, terms are to be understood according toconventional usage by those of ordinary skill in the relevant art

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

As used herein, the term “attached” signifies a stable covalent bond,certain preferred points of attachment being apparent to those ofordinary skill in the art.

The terms “halogen” or “halo” include fluorine, chlorine, bromine, andiodine. Additionally, terms such as “haloalkyl” are meant to includemonohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedchain, or combination thereof, which can be fully saturated, mono- orpolyunsaturated and can include di- and multivalent radicals, having thenumber of carbon atoms designated (i.e., C₁-C₁₀ means one to tencarbons). Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs andisomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. An unsaturated alkyl group is one having one or more double bondsor triple bonds. Examples of unsaturated alkyl groups include, but arenot limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. Accordingly,the term “alkyl” can refer to C₁-C₁₆ straight chain saturated, C₁-C₁₆branched saturated, C₃-C₈ cyclic saturated and C₁-C₁₆ straight chain orbranched saturated aliphatic hydrocarbon groups substituted with C₃-C₈cyclic saturated aliphatic hydrocarbon groups having the specifiednumber of carbon atoms. For example, this definition shall include butis not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu),pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr),isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl,neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopropylmethyl, and the like.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the compoundsdisclosed herein. A “lower alkyl” or “lower alkylene” is a shorter chainalkyl or alkylene group, generally having eight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, consisting of at least one carbon atom and atleast one heteroatom selected from the group consisting of O, N, P, Si,and S, and wherein the nitrogen, phosphorus, silicon, and sulfur atomscan optionally be oxidized, and the nitrogen heteroatom can optionallybe quaternized. The heteroatom(s) O, N, P, S, and Si can be placed atany interior position of the heteroalkyl group or at the position atwhich the alkyl group is attached to the remainder of the molecule.Examples include, but are not limited to: —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two heteroatomscan be consecutive, such as, for example, —CH₂—NH—OCH₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,and the like. Examples of heterocycloalkyl include, but are not limitedto, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The term “alkenyl” includes C₂-C₁₆ straight chain unsaturated, C₂-C₁₁branched unsaturated, C₅-C₈ unsaturated cyclic, and C₂-C₁₆ straightchain or branched unsaturated aliphatic hydrocarbon groups substitutedwith C₃-C₈ cyclic saturated and unsaturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. Double bonds can occur inany stable point along the chain and the carbon-carbon double bonds canhave either the cis or trans configuration. For example, this definitionshall include but is not limited to ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl,1-pentenyl-3-cyclohexenyl, and the like. Similarly, “heteroalkenyl”refers to heteroalkyl having one or more double bonds.

The term “alkynyl” refers in the customary sense to alkyl additionallyhaving one or more triple bonds. The term “cycloalkenyl” refers tocycloalkyl additionally having one or more double bonds. The term“heterocycloalkenyl” refers to heterocycloalkyl additionally having oneor more double bonds.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”) and below terms(e.g., “aryl,” and “heteroaryl”) includes both substituted andunsubstituted forms of the indicated radical. Preferred substituents foreach type of radical are provided herein.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ≡N, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″)═NR′″, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN, and —NO₂ in a number ranging fromzero to (2m′+1), where m′ is the total number of carbon atoms in suchradical. R′, R″, and R′″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxygroups, or arylalkyl groups. When a compound disclosed herein includesmore than one R group, for example, each of the R groups isindependently selected as are each R′, R″, and R′″ group when more thanone of these groups is present. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 4-,5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is notlimited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussionof substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CO NR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NRSO₂R′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂,fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging fromzero to the total number of open valences on the aromatic ring system;and where R′, R″, and R′″ are preferably independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. When acompound disclosed herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, andR′″ groups when more than one of these groups is present.

Two or more substituents can optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringcan optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring can optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed can optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring can optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si). The heteroatom can itself be substituted with an alkyl oraryl group when the heteroatom is N, P, or Si.

The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy,cyclohexyloxy) represents an alkyl group as defined above having theindicated number of carbon atoms attached through an oxygen bridge(—O—).

The term “alkylthio” (e.g. methylthio, ethylthio, propylthio,cyclohexylthio and the like) represents an alkyl group as defined abovehaving the indicated number of carbon atoms attached through a sulfurbridge (—S—).

The term “alkylamino” represents one or two alkyl groups as definedabove having the indicated number of carbon atoms attached through anamine bridge. The two alkyl groups can joined together with the nitrogento which they are attached, thereby forming a cyclic system containing 3to 8 carbon atoms with or without one C₁-C₁₆alkyl, arylC₀-C₁₆alkyl, orC₀-C₁₆alkylaryl substituent.

The term “alkylaminoalkyl” represents an alkylamino group attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term “alkyloxy(alkyl)amino” (e.g. methoxy(methyl)amine,ethoxy(propyl)amine) represents an alkyloxy group as defined aboveattached through an amino group, the amino group itself having an alkylsubstituent.

The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl,3-hexylcarbonyl) represents an alkyl group as defined above having theindicated number of carbon atoms attached through a carbonyl group.

The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy,3-pentenylcarboxy) represents an alkylcarbonyl group as defined abovewherein the carbonyl is in turn attached through an oxygen.

The term “alkylcarboxyalkyl” represents an alkylcarboxy group attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term “alkylcarbonylamino” (e.g. hexylcarbonylamino,cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) represents analkylcarbonyl group as defined above wherein the carbonyl is in turnattached through the nitrogen atom of an amino group.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain from one to four heteroatoms selected from N, O, and S,wherein the nitrogen and sulfur atoms are optionally oxidized, and thenitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl”includes fused ring heteroaryl groups (i.e., multiple rings fusedtogether wherein at least one of the fused rings is a heteroaromaticring). A 5,6-fused ring heteroarylene refers to two rings fusedtogether, wherein one ring has 5 members and the other ring has 6members, and wherein at least one ring is a heteroaryl ring. Likewise, a6,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 6 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,5-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 5 members, and wherein at least one ringis a heteroaryl ring. A heteroaryl group can be attached to theremainder of the molecule through a carbon or heteroatom. Non-limitingexamples of aryl and heteroaryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, benzodioxan-2-yl, benzodioxan-5-yl,benzodioxan-6-yl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl,1,2,4-oxadiazin-3-yl, 1,2,4-oxadiazin-5-yl, 1,2,4-thiazin-3-yl, and1,2,4-thiazin-5-yl. Substituents for each of the above noted aryl andheteroaryl ring systems are selected from the group of acceptablesubstituents described below. An “arylene” and a “heteroarylene,” aloneor as part of another substituent, mean a divalent radical derived froman aryl and heteroaryl, respectively. Accordingly, the term “aryl” canrepresent an unsubstituted, mono-, di- or trisubstituted monocyclic,polycyclic, biaryl and heterocyclic aromatic groups covalently attachedat any ring position capable of forming a stable covalent bond, certainpreferred points of attachment being apparent to those skilled in theart (e. g. 3-indolyl, 4-imidazolyl). The aryl substituents areindependently selected from the group consisting of halo, nitro, cyano,trihalomethyl, C₁₋₁₆alkyl, arylC₁₋₁₆alkyl, C₀₋₁₆alkyloxyC₀₋₁₆alkyl,arylC₀₋₁₆alkyloxyC₀₋₁₆alkyl, C₀₋₁₆alkylthioC₀₋₁₆alkyl,arylC₀₋₁₆alkylthioC₀₋₁₆alkyl, C₀₋₁₆alkylaminoC₀₋₁₆alkyl,arylC₀₋₁₆alkylaminoC₀₋₁₆alkyl, di(arylC₁₋₁₆alkyl)aminoC₀₋₁₆alkyl,—C₁₋₁₆alkylcarbonylC₀₋₁₆alkyl, arylC₁₋₁₆alkylcarbonylC₀₋₁₆alkyl,—C₁₋₁₆alkylcarboxyC₀₋₁₆alkyl, arylC₁₋₁₆alkylcarboxyC₀₋₁₆alkyl,—C₁₋₁₆alkylcarbonylaminoC₀₋₁₆alkyl,arylC₁₋₁₆alkylcarbonylaminoC₀₋₁₆alkyl, —C₀₋₁₆alkylCOOR₄,—C₀₋₁₆alkylCONR₅R₆ wherein R₄, R₅ and R₆ are independently selected fromhydrogen, C₁-C₁₁alkyl, arylC₀-C₁₁alkyl, or R₅ and R₆ are taken togetherwith the nitrogen to which they are attached forming a cyclic systemcontaining 3 to 8 carbon atoms with or without one C₁₋₁₆alkyl,arylC₀-C₁₆alkyl, or C₀-Cl₁₆alkylaryl substituent.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the terms “arylalkyl,” “aralkyl” and thelike are meant to include those radicals in which an aryl group isattached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, andthe like) including those alkyl groups in which a carbon atom (e.g., amethylene group) has been replaced by, for example, an oxygen atom(e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, andthe like), or a sulfur atom. Accordingly, the terms “arylalkyl” and thelike (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl,pyridylcyclopentyl) represents an aryl group as defined above attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is an alkyl group as defined above. R′ canhave a specified number of carbons (e.g., “C₁-C₄ alkylsulfonyl”).

The term “carbonyloxy” represents a carbonyl group attached through anoxygen bridge.

In the above definitions, the terms “alkyl” and “alkenyl” can be usedinterchangeably in so far as a stable chemical entity is formed, aswould be apparent to those skilled in the art.

The term “linker” refers to attachment groups interposed betweensubstituents, e.g., R¹, R², R³, R⁴ or R⁵ described herein, e.g., Formula(I) and generically referred to as R^(n), and the group which issubstituted. In some embodiments, the linker includes amido (—CONH—R^(n)or —NHCO—R^(n)), thioamido (—CSNH—R^(n) or —NHCS—R^(n)), carboxyl(—CO₂—R^(n) or —OCOR^(n)), carbonyl (—CO—R^(n)), urea (—NHCONH—R^(n)),thiourea (—NHCSNH—R^(n)), sulfonamido (—NHSO₂—R^(n) or —SO₂NH—R^(n)),ether (—O—R^(n)), sulfonyl (—SO₂—R^(n)), sulfoxyl (—SO—R^(n)), carbamoyl(—NHCO₂—R^(n) or —OCONH—R^(n)), or amino (—NHR^(n)) linking moieties.

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, oxo, halogen, —COOH,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, —COOH,            unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen,                —COOH, unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from:            -   oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, —COOH,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, and unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2-20-membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 4-8-membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2-8-memberedheteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted5-7-membered heterocycloalkyl

The term “about” used in the context of a numeric value indicates arange of +/−10% of the numeric value, unless expressly indicatedotherwise.

II. Compounds

In one aspect, there is provided a compound with structure of Formula(I):

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.Compounds of Formula (I) have substituent groups according to thefollowing:

L¹ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—, —NHSO₂—, or —NR⁶—;

R¹ is hydrogen, a halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted heterocycloalkenyl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl;

L² is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—, —NHSO₂—, or —NR⁶;

R² is a hydrogen, a halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted heterocycloalkenyl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheterdoaryl;

L³ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, or —O—;

R³ is a hydrogen, a halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;

L⁴ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—, —NHSO₂—, or —NR⁶;

R⁴ is hydrogen, a halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted heterocycloalkenyl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl;

L⁵ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene or —O—;

R⁵ is hydrogen, halogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and

R⁶ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl;

provided that if the pyrazole ring is connected to the 3-position of thepyridone ring, either L³ is not a bond or R³ is not hydrogen.

In some embodiments, the compound is a pharmaceutically acceptable salt,ester, solvate, or prodrug of a compound of Formula (I). In someembodiments, the compound is not an ester, not a solvate, and not aprodrug.

Further to any embodiment above wherein the compound has the structureof Formula (I), in some embodiments, L¹ is —S—, —NR⁶—, substituted orunsubstituted alkylene, or substituted or unsubstituted heteroalkylene,where R⁶ is previously described, and R¹ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, substituted or unsubstituted heteroaryl,or substituted or unsubstituted heterocycloalkyl. In some embodiments,R¹ is substituted or unsubstituted phenyl. In some embodiments, R¹ isunsubstituted phenyl. In some embodiments, R¹ is a substituted orunsubstituted pyridyl. In some embodiments, R¹ is a substituted orunsubstituted pyridazinyl. In some embodiments, R¹ is a substituted orunsubstituted pyrimidinyl. In some embodiments, R¹ is a substituted orunsubstituted thienyl. In some embodiments, R¹ is a substituted orunsubstituted furyl. In some embodiments, R¹ is a substituted orunsubstituted thiazoyl. In some embodiments, R¹ is an unsubstitutedpyridyl. In some embodiments, R¹ is an unsubstituted pyridazinyl. Insome embodiments, R¹ is an unsubstituted pyrimidinyl. In someembodiments, R¹ is an unsubstituted thienyl. In some embodiments, R¹ isa chloro-substituted thienyl. In some embodiments, R¹ is5-chloro-thien-2-yl. In some embodiments, R¹ is a chloro-substitutedthiazoyl. In some embodiments, R¹ is an unsubstituted furyl.

Further to any embodiment above wherein the compound has the structureof Formula (I), in some embodiments, L² is a bond. In some embodiments,R² is hydrogen. In some embodiments, L² is a bond, and R² is hydrogen Insome embodiments, L² is substituted or unsubstituted alkylene or —C(O)—,and R² is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl. In someembodiments, R² is substituted or unsubstituted tert-butyl. In someembodiments, R² is substituted or unsubstituted cyclopropyl. R² issubstituted or unsubstituted bicycloalkyl. In some embodiments, R² issubstituted or unsubstituted tetrahydropyranyl. In some embodiments, R²is substituted or unsubstituted piperidinyl. In some embodiments, R² isa substituted or unsubstituted morpholinyl. In some embodiments, R² is asubstituted or unsubstituted oxanyl. In some embodiments, R² is asubstituted or unsubstituted oxetanyl. In some embodiments, R² is anunsubstituted morpholinyl. In some embodiments, R² is an unsubstitutedoxanyl. In some embodiments, R² is an unsubstituted oxetanyl. In someembodiments, R² is substituted or unsubstituted benzodioxinyl. In someembodiments, R² is substituted or unsubstituted phenyl. In someembodiments, R² is a substituted or unsubstituted pyridyl. In someembodiments, R² is a substituted or unsubstituted pyridazinyl. In someembodiments, R² is a substituted or unsubstituted pyrimidinyl. In someembodiments, R² is a substituted or unsubstituted pyrazinyl. In someembodiments, R² is a substituted or unsubstituted thienyl. In someembodiments, R² is a substituted or unsubstituted furyl. In someembodiments, R² is a substituted or unsubstituted thiazole. In someembodiments, R² is an unsubstituted pyridyl. In some embodiments, R² isan unsubstituted pyridazinyl. In some embodiments, R² is anunsubstituted pyrimidinyl. In some embodiments, R² is an unsubstitutedthienyl. In some embodiments, R² is a chloro-substituted thienyl. Insome embodiments, R² is an unsubstituted furyl. In some embodiments, R²is a substituted or unsubstituted oxazole. In some embodiments, R² is asubstituted or unsubstituted isothiazole. In some embodiments, R² is asubstituted or unsubstituted isoxazole. In some embodiments, R² is asubstituted or unsubstituted thiadiazole. In some embodiments, R² is asubstituted or unsubstituted oxadiazole. In some embodiments, R² is anunsubstituted morpholinyl. In some embodiments, R² is an unsubstitutedoxanyl. In some embodiments, R² is an unsubstituted oxetanyl. In someembodiments, R² is substituted or unsubstituted benzodioxinyl. In someembodiments, R² is substituted or unsubstituted naphthyl. In someembodiments, R² is unsubstituted benzodioxinyl. In some embodiments, R²is unsubstituted naphthyl.

In some embodiments, R² is unsubstituted tert-butyl. In someembodiments, R² is unsubstituted phenyl. In some embodiments, R² is2-fluorophenyl. In some embodiments, R² is 2-chlorophenyl. In someembodiments, R² is 2-methoxyphenyl. In some embodiments, R² is2,4-dimethoxyphenyl. In some embodiments, R² is 2-cyclopropoxyphenyl. Insome embodiments, R² is 2-aminophenyl. In some embodiments, R² isphenyl-2-carboxylic acid. In some embodiments, R² isphenyl-2-carboxamide. In some embodiments, R² is 3-fluorophenyl. In someembodiments, R² is 3-chlorophenyl. In some embodiments, R² is3-aminophenyl. In some embodiments, R² is phenyl-3-carboxylic acid. Insome embodiments, R² is phenyl-3-carboxamide. In some embodiments, R² is3-(hydroxymethyl)phenyl. In some embodiments, R² is 4-fluorophenyl. Insome embodiments, R² is 4-chlorophenyl. In some embodiments, R² isphenyl-4-carboxylic acid. In some embodiments, R² isphenyl-4-carboxamide. In some embodiments, R² is4-(hydroxymethyl)phenyl. In some embodiments, R² is an unsubstitutedpyridyl. In some embodiments, R² is unsubstituted pyridazinyl. In someembodiments, R² is unsubstituted pyrimidinyl. In some embodiments, R² isunsubstituted pyrazinyl. In some embodiments, R² is unsubstitutedthienyl. In some embodiments, R² is thien-2-yl. In some embodiments, R²is thien-3-yl. In some embodiments, R² is unsubstituted furyl. In someembodiments, R² is fur-2-yl. In some embodiments, R² is fur-3-yl. Insome embodiments, R² is unsubstituted thiazole. In some embodiments, R²is 1,3-thiazol-2-yl. In some embodiments, R² is 1,3-thiazol-4-yl. Insome embodiments, R² is 1,3-thiazol-5-yl. In some embodiments, R² isunsubstituted oxazole. In some embodiments, R² is 1,3-oxazol-2-yl. Insome embodiments, R² is 1,3-oxazol-4-yl. In some embodiments, R² is1,3-oxazol-5-yl. In some embodiments, R² is unsubstituted isothiazole.In some embodiments, R² is unsubstituted isoxazole. In some embodiments,R² is unsubstituted thiadiazole. In some embodiments, R² isunsubstituted oxadiazole.

Further to any embodiment above wherein the compound has the structureof Formula (I), in some embodiments, R³ is halogen, and L³ is a bond. Insome embodiments, L³ is a bond, and R³ is substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. In someembodiments, L³ and R³ are attached to the pyridone nucleus such thatthere may be single or multiple instances of L³ and R³, wherein themultiple instances of L³ and R³ can be independent of each other, andthey can be independently attached at one or more of the three opensites of the pyridone moiety. In some embodiments, there is one instanceof L³ and R³. In some embodiments, there are two instances of L³ and R³.In some embodiments, there are three instances of L³ and R³.

Further to any embodiment above wherein the compound has the structureof Formula (I), in some embodiments, R⁴ is hydrogen and L⁴ is a bond. Insome embodiments, L⁴ is a bond, or substituted or unsubstitutedalkylene, and R⁴ is substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, substituted or unsubstitutedheterocycloalkyl. In some embodiments, R⁴ is substituted orunsubstituted phenyl, or substituted or unsubstituted thienyl. In someembodiments, R⁴ is unsubstituted phenyl. In some embodiments, R⁴ isunsubstituted thienyl. In some embodiments, R⁴ is a chloro-substitutedthienyl. In some embodiments, R⁴ is substituted or unsubstitutedpyridyl, or substituted or unsubstituted pyridazinyl. In someembodiments, R⁴ is unsubstituted pyridyl. In some embodiments, R⁴ isunsubstituted pyridazinyl. In some embodiments, R⁴ is substituted orunsubstituted pyrimidinyl, or substituted or unsubstituted furyl. Insome embodiments, R⁴ is unsubstituted pyrimidinyl. In some embodiments,R⁴ is unsubstituted furyl. In some embodiments, R⁴ is substituted orunsubstituted morpholinyl, or substituted or unsubstituted oxanyl, orsubstituted or unsubstituted oxetanyl. In some embodiments, R⁴ isunsubstituted morpholinyl. In some embodiments, R⁴ is unsubstitutedoxanyl. In some embodiments, R⁴ is unsubstituted oxetanyl. In someembodiments, R⁴ is substituted or unsubstituted benzodioxinyl, orsubstituted or unsubstituted naphthyl. In some embodiments, R⁴ isunsubstituted benzodioxinyl. In some embodiments, R⁴ is unsubstitutednaphthyl.

Further to any embodiment above wherein the compound has the structureof Formula (I), in some embodiments, L⁵ is a bond, and R⁵ is hydrogen orhalogen.

The pyridone can be substituted with the pyrazolyl group at anyavailable position, thus leading to the various possiblepyridone-pyrazole isomers. Accordingly, in some embodiments, there isprovided a compound according to Formula (I), with structures of any ofFormulae (IIa), (IIIa), (IVa), or (Va), according to the following:

In some embodiments, there is provided a compound according to any ofFormulae (IIa), (IIIa), (IVa), or (Va) and their embodiments, wherein L²is a bond and R² is hydrogen, providing a respective compound withstructure of Formulae (IIb), (IIIb), (IVb), or (Vb), according to thefollowing:

In some embodiments, there is provided a compound according to any ofFormulae (IIa), (IIIa), (IVa), or (Va) and their embodiments, wherein L²is a bond, R² is hydrogen, L⁴ is a bond, and R⁴ is a hydrogen, providinga respective compound with structure of Formulae (IIc), (IIIc), (IVc),or (Vc), according to the following:

In some embodiments, the pyridone moiety of any of Formulae (IIa),(IIIa), (IVa), or (Va) can be substituted with the L³-R³ groups at anyavailable position, thus leading to the various possible substitutedpyridone-pyrazole isomers. Accordingly, in some embodiments, there isprovided a compound according to Formula (I), with structures of any ofFormulae (VIa), (VIb), (VIc), or (VId), according to the following:

Exemplary compounds, e.g., multisubstituted aromatic compounds, inaccordance with the present disclosure are provided herein. In Tables Aand B following, compound (Cmpd) number, chemical name (i.e.,International Union of Pure and Applied Chemistry [IUPAC] name),calculated molecular weight (MW) and biological activity (i.e.,inhibition activity in thrombin and KLKB1 assays) are disclosed.

For Table A following, the disclosed compounds were assayed forinhibition of the protease activity of thrombin and KLKB1 as describedherein. In Table A, the level of inhibition in the thrombin and KLKB1assays are indicated as follows: a IC₅₀<0.1 μM; b: 0.1 μM<IC₅₀<1 μM; c:1 μM<IC₅₀<10 μM; d: 10 μM<IC₅₀<100 μM; e: IC₅₀≥100 μM. Accordingly, insome embodiments, there is provided a compound as expressly set forth inTable A as follows:

TABLE A Entry Thrombin KLKB1 No. IUPAC name MW Activity Activity 13-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 476 a cdimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1,2-dihydropyridin-2-one 2 3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2-467 a d dimethylpropanoyl)-1H-pyrazol-3-yl)-5-phenyl-1,2-dihydropyridin-2-one 3 3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2-518 b b methoxybenzoyl)-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one 43-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 415 a bcarbonyl)-1H-pyrazol-3-yl)-5-methyl-1,2-dihydropyridin- 2-one 53-bromo-5-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 520 b cmethoxybenzoyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one 63-bromo-5-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 386 e epyrazol-3-yl)-1,2-dihydropyridin-2-one 73-bromo-6-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 480 b d(furan-3-carbonyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2- one 84-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 391 a cdimethylpropanoyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2- one 94-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 449 a cdimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-methoxyethyl)-1,2-dihydropyridin-2-one 104-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 482 a cdimethylpropanoyl)-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one 114-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 482 a bdimethylpropanoyl)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one 124-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 518 a ddimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 134-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 476 c edimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1,2-dihydropyridin-2-one 14 4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2-467 b d methoxybenzoyl)-1H-pyrazol-3-yl)-6-ethenyl-1,2-dihydropyridin-2-one 154-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-2- 478 c ecarbonyl)-1H-pyrazol-3-yl)-6-(pyridin-3-yl)-1,2- dihydropyridin-2-one 164-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 401 a ccarbonyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one 174-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 459 a ccarbonyl)-1H-pyrazol-3-yl)-1-(2-methoxyethyl)-1,2- dihydropyridin-2-one18 4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 492 a bcarbonyl)-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one 194-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 492 a acarbonyl)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one 204-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 528 b ccarbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 214-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(furan-3- 514 a bcarbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)ethyl]-1,2-dihydropyridin-2-one 224-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 417 a bcarbonyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one 234-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 475 a bcarbonyl)-1H-pyrazol-3-yl)-1-(2-methoxyethyl)-1,2- dihydropyridin-2-one24 4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 508 a acarbonyl)-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one 254-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 508 a acarbonyl)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one 264-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 544 b ccarbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 274-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 530 a bcarbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)ethyl]-1,2-dihydropyridin-2-one 284-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 493 e ecarbonyl)-1H-pyrazol-3-yl)-6-phenyl-1,2-dihydropyridin-2- one 294-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H-pyrazol-3-yl)- 307 e e1,2-dihydropyridin-2-one 304-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H-pyrazol-3-yl)- 398 e e1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one 315-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 391 b ddimethylpropanoyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2- one 325-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 518 a edimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 335-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 468 b ddimethylpropanoyl)-1H-pyrazol-3-yl)-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one 345-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 405 b ddimethylpropanoyl)-1H-pyrazol-3-yl)-3-methyl-1,2- dihydropyridin-2-one35 5-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 467 c ddimethylpropanoyl)-1H-pyrazol-3-yl)-3-phenyl-1,2- dihydropyridin-2-one36 5-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2- 466 b bmethoxybenzoyl)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile 375-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(thiophene-3- 417 b ccarbonyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one 385-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H-pyrazol-3-yl)- 307 e e1,2-dihydropyridin-2-one 395-bromo-3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 470 a ddimethylpropanoyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2- one 405-bromo-3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 597 a cdimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 415-bromo-3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1- 496 a b(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin- 2-one 425-bromo-3-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H- 386 e dpyrazol-3-yl)-1,2-dihydropyridin-2-one 436-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 391 a cdimethylpropanoyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2- one 446-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 482 a edimethylpropanoyl)-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one 456-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 518 a edimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 466-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 417 a ddimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1,2- dihydropyridin-2-one47 6-(5-[(5-chlorothiophen-2-yl)methyl]amino-1H-pyrazol-3-yl)- 307 e e1,2-dihydropyridin-2-one 486-bromo-4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 470 a ddimethylpropanoyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2- one

Compounds disclosed herein also include racemic mixtures, stereoisomersand mixtures of the compounds, including isotopically-labeled andradiolabeled compounds. See e.g., Goding, 1986, MONOCLONAL ANTIBODIESPRINCIPLES AND PRACTICE; Academic Press, p. 104. Such isomers can beisolated by standard resolution techniques, including e.g., fractionalcrystallization, chiral chromatography, and the like. See e.g., Eliel,E. L. & Wilen S. H., 1993, STEREOCHEMISTRY IN ORGANIC COMPOUNDS; JohnWiley & Sons, New York.

In some embodiments, compounds disclosed herein have asymmetric centersand can occur as racemates, racemic mixtures, and as individualenantiomers or diastereoisomers, with all isomeric forms as well asmixtures thereof being contemplated for use in the compounds and methodsdescribed herein. The compounds contemplated for use in the compoundsand methods described herein do not include those that are known in theart to be too unstable to synthesize and/or isolate.

The compounds disclosed herein can also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds can be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations of the compoundsdisclosed herein, whether radioactive or not, are encompassed within thecontemplated scope.

In some embodiments, metabolites of the compounds disclosed herein areuseful for the methods disclosed herein.

In some embodiments, compounds contemplated herein are provided in theform of a prodrug. The term “prodrug” refers to a compound that can beconverted into a compound (e.g., a biologically active compound)described herein in vivo. Prodrugs can be useful for a variety of reasonknown in the art, including e.g., ease of administration due e.g., toenhance bioavailability in oral administration, and the like. Theprodrug can also have improved solubility in pharmaceutical compositionsover the biologically active compounds. An example, without limitation,of a prodrug is a compound which is administered as an ester (i.e., the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water solubility is beneficial. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in DESIGN OF PRODRUGS (ed. H. Bundgaard,Elsevier, 1985), which is hereby incorporated herein by reference forthe limited purpose describing procedures and preparation of suitableprodrug derivatives.

Accordingly, in some embodiments, compounds contemplated herein areprovided in the form of a prodrug ester. The term “prodrug ester” refersto derivatives of the compounds disclosed herein formed by the additionof any of a variety of ester-forming groups, e.g., groups known in theart, that are hydrolyzed under physiological conditions. Examples ofprodrug ester groups include pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of prodrug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975); andBIOREVERSIBLE CARRIERS IN DRUG DESIGN: THEORY AND APPLICATION, edited byE. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examplesof esters useful as prodrugs for compounds containing carboxyl groups).Each of the above-mentioned references is herein incorporated byreference for the limited purpose of disclosing ester-forming groupsthat can form prodrug esters.

In some embodiments, prodrugs can be slowly converted to the compoundsdescribed herein useful for the methods described herein when placed ina transdermal patch reservoir with a suitable enzyme or chemicalreagent.

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of contemplated compounds. Certain compounds of the presentinvention can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the compounds and methodscontemplated herein and are intended to be within the scope disclosedherein.

III. Biological Activities

In some embodiments, compounds described herein exhibit inhibitoryactivity against thrombin with activities ≥1 μM, e.g., about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 μM, oreven greater. In some embodiments, the compounds exhibit inhibitoryactivity against thrombin with activities between 0.1 μM and 1 μM, e.g.,about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 μM. In someembodiments, compounds described herein exhibit inhibitory activityagainst thrombin with activities ≤0.1 μM, e.g., about 1, 2, 5, 10, 15,20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using acombination of any of the values recited herein as upper and/or lowerlimits are also contemplated, for example, but not limited to, 1-10 nM,10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even500-1000 μM. In some embodiments, the inhibitory activity is in therange of about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200μM, 200-500 μM, or even 500-1000 μM. It is understood that for purposesof quantification, the terms “activity,” “inhibitory activity,”“biological activity,” “thrombin activity” and the like in the contextof an inhibitory compound disclosed herein can be quantified in avariety of ways known in the art. Unless indicated otherwise, as usedherein such terms refer to IC₅₀ in the customary sense (i.e.,concentration to achieve half-maximal inhibition).

Inhibitory activity against thrombin in turn inhibits the bloodcoagulation process. Accordingly, compounds disclosed herein areindicated in the treatment or management of thrombotic disorders. Insome embodiments, a dose or a therapeutically effective dose of acompound disclosed herein will be that which is sufficient to achieve aplasma concentration of the compound or its active metabolite(s) withina range set forth herein, e.g., about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM, preferablyabout 1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound byany theory, it is believe that such compounds are indicated in thetreatment or management of thrombotic disorders.

In some embodiments, compounds described herein exhibit inhibitoryactivity against KLK1 and/or KLKB1 with activities between 1 μM and 10μM, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 μM. In some embodiments,compounds described herein exhibit inhibitory activity against KLK1and/or KLKB1 with activities ≥10 μM, e.g., about 10, 20, 50, 100, 150,200, 300, 400, 500, 600, 700, 800, 900, 1000 μM or even greater. In someembodiments, compounds described herein exhibit inhibitory activityagainst KLK1 and/or KLKB1 with activities ≤1 μM, e.g., about 900, 800,700, 600, 500, 400, 300, 200, 100, 50 nM or even lower. Ranges of valuesusing a combination of any of the values recited herein as upper and/orlower limits are also contemplated, for example, but not limited to,1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500μM, or even 500-1000 μM. In some embodiments, the inhibitory activity isin the range of about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM,100-200 μM, 200-500 μM, or even 500-1000 μM. It is understood that forpurposes of quantification, the terms “activity,” “inhibitory activity,”“biological activity,” “KLK1 activity”, “KLKB1 activity” and the like inthe context of an inhibitory compound disclosed herein can be quantifiedin a variety of ways known in the art. Unless indicated otherwise, asused herein such terms refer to IC₅₀ in the customary sense (i.e.,concentration to achieve half-maximal inhibition).

Inhibitory activity against KLKB1 has an effect on the coagulationcascade and the inflammatory response. Thus, it has been proposed thatKLKB1 inhibitors can be useful in the treatment of thrombotic andfibrinolytic diseases and disease conditions.

Accordingly, compounds disclosed herein are indicated in the treatmentor management of a variety of diseases or disorders. In someembodiments, a dose or a therapeutically effective dose of a compounddisclosed herein will be that which is sufficient to achieve a plasmaconcentration of the compound or its active metabolite(s) within a rangeset forth herein, e.g., about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM,10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM, preferably about1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound by anytheory, it is believe that such compounds are indicated in the treatmentor management of diseases associated with thrombin or kallikrein.

IV. Methods of Treating and Preventing Disease

Serine proteases are a large family of enzymes with diverse biologicalfunctions, their commonality being the presence and critical function ofthe active-site serine residue. Their central function is the catalyticscission of peptide bond substrates via a Ser, His, Asp triad within theactive site (Kraut, J. Annual Review of Biochemistry 1977, 46, 331-358).

The present disclosure relates to compounds, e.g.,3-pyrazolyl-substituted pyridone compounds, which exhibit biologicalactivity, e.g., inhibitory action, against serine proteases, includingthrombin and various kallikreins.

Kallikrein-related diseases or disorders are biological conditionsassociated with or moderated by kallikrein. They include, but are notlimited by, those conditions associated with biological pathways thatare moderated by tissue and plasma kallikrein. An example of such apathway is the kallikrein-kinin system (Moreau, M. E. 2005, Journal ofPharmacological Sciences, 99, 6). Kallikrein-related diseases ordisorders include, but are not limited to, fibrosis, inflammation,thrombosis, hereditary angioedema, skin disorders, cancer, andophthalmic diseases. Ophthalmic diseases include, but are not limitedto, diabetic macular edema, diabetic retinopathy, and age-relatedmacular degeneration.

Diabetic Macular Edema.

In rodent models, it has been shown that activation of KLKB1 in the eyeincreases retinal vascular permeability; whereas inhibition of thekallikrein-kinin system reduces retinal leakage induced by diabetes andhypertension. These findings suggest that intraocular activation of theKLKB1 pathway can contribute to excessive retinal vascular permeabilitythat can lead to diabetic macular edema. Thus, evidence suggests thatKLKB1 inhibitors can provide a new therapeutic opportunity to reduceretinal vascular permeability (Feener, E. P. 2010, Curr Diab Rep 10,270).

Hereditary Angioedema.

Ecallantide (Kalbitor) is a 60-amino acid recombinant protein that actsas a potent reversible inhibitor of KLKB1 (Schneider L, et al. 2007, JAllergy Clin Immunol, 120, 416) and has been approved by the FDA for thetreatment of acute attacks of hereditary angioedema (HAE). Thus plasmakallikrein inhibition can be a useful treatment for HAE, and there isstrong interest in the development of plasma kallikrein inhibitors as atherapy for HAE.

Cerebral Hemorrhage.

Hyperglycemic and diabetic individuals have an elevated risk ofhemorrhage during thrombolytic therapy. In rodent models ofintracerebral hemorrhage (ICH), it has been shown that KLKB1 inhibitionor knockout reduces this effect. While the mechanism is not fullyunderstood, this evidence suggests that plasma kallikrein inhibitors canbe useful in the treatment of cerebral hemorrhage (Feener, E. P. CurrDiab Rep 2010, 10, 270).

Ischemic Stroke and Traumatic Brain Injury.

Plasma kallikrein and Factor XIIa inhibitors have been shown to beneuroprotective in animal models of acute ischemic stroke and traumaticbrain injury, reducing edema formation, inflammation, and thrombosis(Albert-Weißenberger C, Sirén A L, Kleinschnitz C. Prog Neurobiol. 2013,101-102, 65-82). Thus, evidence suggests that plasma kallikreininhibitors can be useful in the treatment of acute ischemic stroke andtraumatic brain injury.

Diabetes.

Plasma kallikrein can also cleave glucagon-like peptide 1 (GLP-1) andneuropeptide Y (NPY), both substrates for dipeptidyl peptidase-4(DPP-4), a validated diabetes drug target. In the case of GLP-1,cleavage by KLKB1 reduces both its potency as well as plasma stability.In the case of NPY, cleavage by KLKB1 reduces its affinity to the Y2 andY5 receptors. Thus, evidence suggests that plasma kallikrein inhibitorscan be useful in the modulation of energy homeostasis and in thetreatment of diabetes. (Feener, E. P. Curr Diab Rep 2010, 10, Feener, E.P. et al., Biol. Chem. 2013, 394, 319).

Gastritis and Peptic Ulcers.

Daiichi Seiyaku Co Ltd received approval in Japan to market cetraxatefor gastritis and peptic ulcers. Cetraxate is reported as a plasmakallikrein inhibitor (WIPO Patent Application WO/2006/108643). Withoutfurther wishing to be bound by any theory, it is reasonable to believethat plasma kallikrein inhibition in general can be useful in thetreatment of gastritis and peptic ulcers.

Skin.

Overexpression of various KLKs in the skin has led to the recognitionthat certain kallikrein inhibitors can be useful for certaindermatological conditions, including atopic dermatitis, psoriasis andrare skin diseases such as Netherton Syndrome (Freitas et al. Bioorganic& Medicinal Chemistry Letters 2012, 22, 6072-6075).

Thrombosis.

Thrombotic diseases are the primary indications for thrombin inhibition,because of thrombin's location in the coagulation cascade and, in turn,the importance of the coagulation cascade in the progression of bloodclotting processes. However, without wishing to be bound by any theory,it is believed the coagulation cascade in general, and thrombin inparticular, is important in a variety other disease states.

It has been discovered that compounds described herein, e.g.,multisubstituted aromatic compounds, exhibit inhibitory action againstthrombin (activated blood-coagulation factor II; EC 3.4.21.5). This, inturn inhibits the blood coagulation process.

This inhibitory action is useful in the treatment of a variety ofthrombotic disorders, such as, but not limited to, acute vasculardiseases such as acute coronary syndromes; venous-, arterial- andcardiogenic thromboembolisms; the prevention of other states such asdisseminated intravascular coagulation, or other conditions that involvethe presence or the potential formation of a blood clot thrombus. Otherindications for methods described herein include the following.

Cancer.

Tissue kallikreins (KLKs) are subdivided into various types, and havebeen extensively investigated in cancer and inflammation biology.Various kallikrein KLKs have been found to be up- or down-regulated invarious cancer types, such as cervical-, testicular-, and non-small-celllung adenocarcinoma (Caliendo et al. J. Med. Chem., 2012, 55, 6669). Ithas been proposed that kallikrein inhibitors, including KLK1 inhibitors,can be useful in certain cancers.

It has long been recognized that cancer progression is accompanied byvenous thrombosis, but it has not been understood how each disease isrelated. From several clinical trials studying the treatment of VTE,meta-analyses have shown that low molecular weight heparins (LMWHs)improve overall survival in subgroups of cancer patients. See e.g.,Zacharski, L. R. & Lee, A. Y., 2008, Expert Opin Investig Drugs,17:1029-1037; Falanga, A. & Piccioli, A., 2005, Current Opinion inPulmonary Medicine, 11:403-407; Smorenburg, S. M., et al., 1999, ThrombHaemost, 82:1600-1604; Hettiarachchi, R. J., et al., 1999, ThrombHaemost, 82:947-952. This finding was substantiated in later clinicaltrials that measured specifically the survival of cancer patients. Seee.g., Lee, A. Y. et al., 2005, J Clin Oncol, 23:2123-2129; Klerk, C. P.et al., J Clin Oncol 2005, 23:2130-2135; Kakkar, A. K., et al., 2004, JClin Oncol, 22:1944-1948; Altinbas, M., et al., 2004, J Thromb Haemost,2:1266-1271.

More recently, researchers have focused on the specific anticancereffect of DTIs. For example, it was shown that heparin significantlyprolonged the survival of patients with limited small cell lung cancer.See e.g., Akl, E. A., et al., 2008, J Exp Clin Cancer Res, 27:4. Otherinvestigators found that systemic use of argatroban reduced tumor massand prolonged survival time in rat glioma models leading to theconclusion that argatroban should be considered as a novel therapeuticfor glioma, a notoriously difficult to treat cancer type. See e.g., Hua,Y., et al., 2005, Acta Neurochir, Suppl 2005, 95:403-406; Hua, Y., etal., 2005, J Thromb Haemost, 3:1917-1923. Very recently, it wasdemonstrated that dabigatran etexilate, a DTI recently FDA-approved (seee.g., Hughes, B., 2010, Nat Rev Drug Discov, 9:903-906) for DVTindications, inhibited both the invasion and metastasis of malignantbreast tumors. See e.g., DeFeo, K. et al., 2010, Thrombosis Research,125 (Supplement 2): S188-S188; Defeo, K., et al., 2010, Cancer BiolTher, 10:1001-1008. Thus, dabigatran etexilate treatment led to a 50%reduction in tumor volume at 4 weeks with no weight loss in treatedmice. Dabigatran etexilate also reduced tumor cells in the blood andliver micrometastases by 50-60%. These investigators concluded thatdabigatran etexilate can be beneficial in not only preventing thromboticevents in cancer patients, but also as adjunct therapy to treatmalignant tumors.

Further, hirudin and the LMWH nadroparin dramatically reduced the numberof lung metastases when administered prior to cancer cell inoculation.See e.g., Hu, L., et al., 2004, Blood, 104:2746-51.

The de novo thrombin inhibitor d-Arg-Oic-Pro-d-Ala-Phe(p-Me) has beenfound to block thrombin-stimulated invasion of prostate cancer cell linePC-3 in a concentration dependent manner. See e.g., Nieman, M. T., etal., 2008, J Thromb Haemost, 6:837-845. A reduced rate of tumor growthwas observed in mice dosed with the pentapeptide through their drinkingwater. The mice also showed reduced fold rate in tumor size and reducedoverall tumor weight compared to untreated mice. Microscopic examinationof treated tumors showed reduced number of large blood vessels thusconcluding that the pentapeptide interfered with tumor angiogenesis.Nieman, M. T., et al., Thromb Haemost, 104:1044-8.

In view of these and related studies, it is suggested thatanticoagulants affect tumor metastasis; that is, angiogenesis, cancercell adhesion, migration and invasion processes. See e.g., Van Noorden,C. J., et al., 2010, Thromb Res, 125 Suppl 2:S77-79.

Fibrosis.

Kallikreins are a subgroup of serine proteases, divided into plasmakallikrein (KLKB1) and tissue kallikreins. KLKB1 liberates kinins(bradykinin and kallidin) from the kininogens, peptides responsible forthe regulation of blood pressure and activation of inflammation. In theContact Activation Pathway of the coagulation cascade, KLKB1 assists inthe conversion of factor XII to factor XIIa (Keel, M.; Trentz, O. Injury2005, 36, 691-709). Factor XIIa converts FXI into FXIa, which in turnactivates FIX, which with its co-factor FVIIIa forms the tenase complex,which finally activates FX to FXa. In the fibrinolysis part of thecoagulation cascade, KLKB1 serves to convert plasminogen to plasmin.Thus, it has been proposed that KLKB1 inhibitors can be useful in thetreatment of thrombotic and fibrinolytic diseases and disease conditions(U.S. Pat. No. 7,625,944; Bird et al. Thrombosis and Hemostasis 2012,107, 1141).

Several studies have shown the utility of anticoagulant therapy infibrotic disorders. For example, in a rat model of CCl₄-induced chronicliver injury, the DTI SSR182289 decreased liver fibrogenesissignificantly after 7 weeks of administration. Similar observations weremade in other studies using the LMWHs nadroparin, tinzaparin,enoxaparin, and dalteparin sodium. See e.g., Duplantier, J. G., et al.,2004, Gut, 53:1682-1687; Abdel-Salam, O. M., et al., 2005, PharmacolRes, 51:59-67; Assy, N., et al., 2007, Dig Dis Sci, 52:1187-1193; Abe,W., et al., 2007, J Hepatol, 46:286-294. Thus a thrombin inhibitor as ananticoagulant can be useful in the treatment of fibrinolytic diseases.

In another example, the DTI melagatran greatly reduced ischemiareperfusion injury in a kidney transplant model in the large white pig.This led to a drastically improved kidney graft survival at 3 months.See e.g., Favreau, F., et al., 2010, Am J Transplant, 10:30-39.

Recent studies have shown that in a bleomycin-induced mouse model ofpulmonary fibrosis, dabigatran etexilate treatment reduced importantprofibrotic events in lung fibroblasts, including the production ofcollagen and connective tissue growth factor. See e.g., Silver, R. M.,et al., 2010, Am. J. Respir. Crit. Care Med., 181:A6780; Bogatkevich, G.S., et al., 2009, Arthritis Rheum, 60:3455-3464.

The above experimental evidence points to a close relationship betweenthrombin and fibrosis and suggests novel therapeutic opportunities forfibrosis using thrombin inhibitors. See e.g., Calvaruso, V., et al.,2008, Gut, 57:1722-1727; Chambers, R. C., 2008, Br J Pharmacol, 153Suppl 1:S367-378; Chambers, R. C. & Laurent, G. J., 2002, Biochem SocTrans, 30:194-200; Howell, D. C., et al., 2001, Am J Pathol,159:1383-1395.

Kallikrein has long been implicated in inflammation (Clements, J. A. TheMolecular Biology of the Kallikreins and Their Roles in Inflammation,Academic Press: San Diego, Calif., 1997; Vol. 5). There is experimentalevidence that KLKB1 is associated with sepsis and inflammatory arthritis(Colman, R. W., 1998, Clinical Reviews in Allergy and Immunology, 16:365). Thus a KLKB1 inhibitor can be useful in the treatment ofinflammatory conditions associated with the kallikrein-kinin system,such as systemic inflammatory response syndrome, sepsis, rheumatoidarthritis, and inflammatory bowel disease.

Age-Related Macular Degeneration.

KLK1 has been linked to blood vessel growth moderated by the VEGFpathway (Miura S., 2003, Hypertension, 41, 1118). Age-related maculardegeneration (AMD) is associated with the proliferation of abnormalblood vessels and VEGF expression (Lopez, P. F., 1996, InvestigativeOphthalmology & Visual Science, 37, 855). Thus, kallikrein inhibitors,including KLK1 inhibitors, have been proposed for the treatment of AMD(US Patent #20120264798; Ferrara, N., 2000, Current Opinion inBiotechnology, 11, 617).

Alzheimer's Disease.

Very recent experiments confirm higher thrombin levels in brainendothelial cells of patients with Alzheimer's disease. While ‘normal’thrombin levels are connected to regulatory CNS functions, thrombinaccumulation in the brain is toxic. It has also been found that theneural thrombin inhibitor Protease Nexin 1 (PN-1) is significantlyreduced in the Alzheimer's disease brain, despite the fact that PN-1mRNA levels are unchanged. These observations have led someinvestigators to suggest that reduction of CNS-resident thrombin willprove useful in Alzheimer's Disease (AD) treatment. See e.g., Vaughan,P. J., et al., 1994, Brain Res, 668:160-170; Yin, X., et al., 2010, Am JPathol, 176:1600-1606; Akiyama, H., et al., 1992, Neurosci Lett,146:152-154.

Multiple Sclerosis.

Investigators found that hirudin treatment in an animal model ofMultiple Sclerosis (MS) showed a dramatic improvement in diseaseseverity. See e.g., Han, M. H., et al., 2008, Nature, 451:1076-1081.Similar results were obtained following treatment with heparin (a DTI)and dermatan sulfate, another coagulation inhibitor. See e.g.,Chelmicka-Szorc, E. & Amason, B. G., 1972, Arch Neurol, 27:153-158;Inaba, Y., et al., 1999, Cell Immunol, 198:96-102. Other evidence showsthat naturally occurring antithrombin III has anti-inflammatory effectsin diseases such as endotoxemia and other sepsis-related conditions. Seee.g., Wiedermann, C. J. & Romisch, J., 2002, Acta Med Austriaca,29:89-92. Naturally occurring thrombin inhibitors are presumablysynthesized in situ and have protective roles in CNS inflammation.Therefore, therapeutic thrombin inhibition has been proposed as apotential MS treatment. See e.g., Luo, W., et al., 2009, In: THROMBIN,Maragoudakis, M. E.; Tsopanoglou, N. E., Eds. Springer New York: 2009;pp 133-159.

Pain.

In a rat pain model with partial lesion of the sciatic nerve,intrathecal hirudin prevented the development of neuropathic pain andcurbed pain responses for 7 days. The investigators found that followinginjury, neuropathic pain was mediated by thrombin generation, which inturn activated PAR-1 receptor in the spinal cord. Hirudin inhibitedthrombin generation and ultimately led to pain relief. See e.g., Garcia,P. S., et al., 2010, Thromb Haemost, 103:1145-1151; Narita, M., et al.,2005, J Neurosci, 25:10000-10009. Researchers hypothesize that thrombinand the PARs are involved not just as part of the coagulation cascade,but in inflammation, nociception and neurodevelopment. Development of aDTI to intersect an unexploited pharmacology will lead to paintherapeutics distinct from opioids and NSAIDs, whose shortcomings arewell documented. See e.g., Garcia 2010, Id.

Accordingly, in a further aspect, there is provided a method fortreating a disease or disorder in a subject in need thereof. The methodincludes administering a compound of any of Formulae (I), (II) or (III)as disclosed herein, a compound as set forth in Table A, or in Table B(Appendix A) pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, or pharmaceutical composition thereof, to a subject inneed thereof in an amount effective to treat the disease or disorder.The terms “therapeutically effective amount,” “amount effective totreat,” “amount effective to prevent” and the like refer to that amountof drug or pharmaceutical agent (e.g., compound or pharmaceuticalcomposition disclosed herein) that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician.

Compounds useful for methods disclosed herein include the compounds setforth for Formulae (I), (II) or (III) and for the compounds set forth inTable A above or in Table B (Appendix A).

In some embodiments, the diseases or disorders are thrombotic disorders.In some embodiments, the thrombotic disorder is acute coronary syndrome,venous thromboembolism, arterial thromboembolism, cardiogenicthromboembolism, disseminated intravascular coagulation, or a blood clotthrombus.

In some embodiments, the diseases or disorders are fibrinolyticdiseases. In some embodiments the disease is a fibrotic disorder. Insome embodiments, the disease is cancer. In some embodiments, thediseases are inflammatory diseases. In some embodiments the disease issepsis. In some embodiments the disease is inflammatory arthritis. Insome embodiments, the disease is diabetic macular edema. In someembodiments, the disease is hereditary angioedema. In some embodiments,the disease is diabetic retinopathy. In some embodiments, the disease isage-related macular degeneration. In some embodiments, the diseases arevarious skin diseases which include but are not limited to atopicdermatitis, psoriasis and rare skin diseases such as Netherton Syndrome.In some embodiments, the diseases or disorder is Alzheimer's disease. Insome embodiments, the disease is multiple sclerosis. In someembodiments, the disease is pain.

In some embodiments, the disease or disorder is cancer. In someembodiments, the cancer is limited small cell lung cancer. In someembodiments, the cancer is a glioma. In some embodiments, the cancer ismalignant breast cancer. In some embodiments, the cancer is amicrometastasis. In some embodiments, the micrometastasis is of theblood or liver. In some embodiments, the cancer is a lung metastasis. Insome embodiments, the cancer is prostatic cancer.

In another aspect, there is provided a method for preventing a diseaseor disorder in a subject. The method includes administering a compoundof any of Formulae (I), (II) or (III) as disclosed herein, compound asset forth in Table A or in Table B (Appendix A), pharmaceuticallyacceptable salt, ester, solvate, or prodrug thereof, or pharmaceuticalcomposition thereof, to a subject in need thereof in an amount effectiveto prevent the disease or disorder.

V. Assays

Compounds described herein can be assayed, by a variety of methods knownin the art and described herein, for inhibition of biological activity,e.g., protease activity, of a variety of proteins, e.g., thrombin,KLKB1, and KLK1.

The KLKB1 kallikrein activity reported herein (e.g., Table A) wasobtained as follows. Human KLKB1 protein was obtained from EnzymeResearch Labs. The chromogenic substrate S-2302 was obtained fromDiaPharma. KLKB1 was assayed in buffer containing 0.05 M Tris (pH 7.4),0.01 M NaCl and 0.2% w/v PEG-8000. The final concentration of enzymeused was 3 nM KLKB1. The final concentration of substrate used was 250μM S-2302 for KLKB1. All assays were performed in 96-well microtiterplates at room temperature (RT). The enzyme and inhibitor werepre-incubated for 10 minutes then substrate was added and read at 405 nmin a SpectraMax Plus Spectrophotometer (Molecular Devices). InhibitorIC₅₀ values were determined by adding test compound as ten point,three-fold serial dilutions in buffer solution, as known in the art. Theplate was read at 10 minutes after substrate addition. The IC₅₀ wascalculated by plotting the percent (%) inhibition against compoundconcentration and fitting the data to a constrained four parametersigmoidal curve, as known in the art.

KLK1 kallikrein activity is obtained as follows. Recombinant humantissue kallikrein (KLK1) is obtained from R&D Systems. Pro-Phe-Arg-AMC(I-1295) substrate is obtained from Bachem. KLK1 enzyme is activated byincubating 0.5 mg/ml KLK1 combined with 0.1 μg/ml thermolysin in abuffer of 0.05 M Tres (pH 7.5), 0.15 M NaCl, and 0.01 M CaCl₂) for onehour at 37° C. The thermolysin is then deactivated by the addition ofequal parts 20 mM 1, 10 phenanthroline solution in water. The activatedKLK1 solution is then added to CHES buffer (0.05 M CHES, 0.15 M NaCl,0.01 M CaCl₂, pH 10) for a final concentration of 5 nM along with thetest article and incubated for 10 minutes. Substrate is then added at aconcentration of 2.75 μM. Substrate activation is read 10 minutes aftersubstrate addition using a Synergy H1 multifunction plate reader(Biotek) programmed with a 360 nm excitation wavelength and a 480 nmemission wavelength. Inhibitor response is established by adding testcompound as ten point, three-fold serial dilutions, as known in the art.The IC₅₀ is calculated by plotting the percent (%) inhibition againstcompound concentration and fitting the data to a constrained fourparameter sigmoidal curve, as known in the art.

The thrombin activity reported herein (e.g., Table A) was obtained asfollows. Human thrombin was obtained from Haematologic Technologies Inc.The chromogenic substrate S-2238 was obtained from DiaPharma. Thrombinwas assayed in buffer containing 0.05 M Tris (pH 7.4), 0.015 M NaCl and0.01% PEG-8000. The final concentration of enzyme used was 3 nMthrombin. The final concentration of substrate used was 125 μM S-2238for thrombin. All assays were performed in 96-well microtiter plates atroom temperature (RT). The enzyme and inhibitor were pre-incubated for10 minutes then substrate was added and read at 405 nm in a SpectraMaxPlus Spectrophotometer (Molecular Devices). Inhibitor IC₅₀ values weredetermined by adding test compound as ten point, three-fold serialdilutions in buffer solution, as known in the art. The plate was read at10 minutes after substrate addition. The IC₅₀ was calculated by plottingthe percent (%) inhibition against compound concentration and fittingthe data to a constrained four parameter sigmoidal curve, as known inthe art.

VI. Pharmaceutical Compositions

In another aspect, there is provided a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptableexcipient. The compound is a compound of any of Formulae (I), (II) or(III) as disclosed herein, a compound as set forth in Table A or inTable B (Appendix A) herein, or pharmaceutically acceptable salt, ester,solvate, or prodrug thereof. In some embodiments, the compound is setforth in Table A or in Table B (Appendix A) herein.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds disclosed herein containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds disclosed herein contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galacturonic acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977,66, 1-19). Certain specific compounds disclosed herein contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

Compounds disclosed herein can exist as salts, such as withpharmaceutically acceptable acids. Accordingly, the compoundscontemplated herein include such salts. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts can be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Pharmaceutically acceptable salts of the compounds above, where a basicor acidic group is present in the structure, are also included withinthe scope of compounds contemplated herein. When an acidic substituentis present, such as —NHSO₃H, —COOH and —P(O)(OH)₂, there can be formedthe ammonium, sodium, potassium, calcium salt, and the like, for use asthe dosage form. Basic groups, such as amino or basic heteroarylradicals, or pyridyl and acidic salts, such as hydrochloride,hydrobromide, acetate, maleate, palmoate, methanesulfonate,p-toluenesulfonate, and the like, can be used as the dosage form.

Also, in the embodiments in which R—COOH is present, pharmaceuticallyacceptable esters can be employed, e. g., methyl, ethyl, tert-butyl,pivaloyloxymethyl, and the like, and those esters known in the art formodifying solubility or hydrolysis characteristics for use as sustainedrelease or prodrug formulations.

A. Formulations

The compounds disclosed herein can be prepared and administered in awide variety of ophthalmic, oral, parenteral, and topical dosage forms.The compounds described herein can be administered by eye drop. Also,compounds described herein can be administered by injection (e.g.intravenously, intramuscularly, intravitreally, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally). As such,compounds described herein can also be administered by intravitrealinjection. Also, the compounds described herein can be administered byinhalation, for example, intranasally. Additionally, the compoundsdisclosed herein can be administered transdermally. It is alsoenvisioned that multiple routes of administration (e.g., intramuscular,oral, ocular) can be used to administer the compounds disclosed herein.

In some embodiments, the compounds disclosed herein can be prepared inliquid pharmaceutical compositions for ocular administration. Thecomposition for ocular use can contain one or more agents selected fromthe group of buffering agents, solubilizing agents, coloring agents,viscosity enhancing agents, and preservation agents in order to producepharmaceutically elegant and convenient preparations.

In some embodiments, the composition for ocular use can containpreservatives for protection against microbiological contamination,including but not limited to benzalkonium chloride and/or EDTA. Otherpossible preservatives include but are not limited to benzyl alcohol,methyl parabens, propyl parabens, and chlorobutanol. Preferably, apreservative, or combination of preservatives, will be employed toimpart microbiological protection in addition to protection againstoxidation of components.

In some embodiments, the compounds disclosed herein can be administeredorally as tablets, aqueous or oily suspensions, lozenges, troches,powders, granules, emulsions, capsules, syrups or elixirs. Thecomposition for oral use can contain one or more agents selected fromthe group of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to produce pharmaceutically elegant andpalatable preparations. Accordingly, there are also providedpharmaceutical compositions comprising a pharmaceutically acceptablecarrier or excipient and one or more compounds disclosed herein.

In some embodiments, tablets contain the acting ingredient in admixturewith non-toxic pharmaceutically acceptable excipients that are suitablefor the manufacture of tablets. These excipients can be, for example,(1) inert diluents, such as calcium carbonate, lactose, calciumphosphate, carboxymethylcellulose, or sodium phosphate; (2) granulatingand disintegrating agents, such as corn starch or alginic acid; (3)binding agents, such as starch, gelatin or acacia; and (4) lubricatingagents, such as magnesium stearate, stearic acid or talc. These tabletscan be uncoated or coated by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate can beemployed.

For preparing pharmaceutical compositions from the compounds disclosedherein, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substance that can also act as diluents,flavoring agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

A compound disclosed herein, in the form of a free compound or apharmaceutically-acceptable pro-drug, metabolite, analogue, derivative,solvate or salt, can be administered, for in vivo application,parenterally by injection or by gradual perfusion over time.Administration can be intravenously, intraperitoneally, intramuscularly,subcutaneously, intracavity, or transdermally. For in vitro studies thecompounds can be added or dissolved in an appropriate biologicallyacceptable buffer and added to a cell or tissue.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds disclosed herein are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampoules areconvenient unit dosages. The compounds disclosed herein can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in thepharmaceuticals compositions and methods disclosed herein include thosedescribed, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub.Co., Easton, Pa.) and WO 96/05309, the teachings of both of which arehereby incorporated by reference.

In some embodiments, preparations for parenteral administration includesterile aqueous or non-aqueous solutions, suspensions, and emulsions.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and injectable organic esterssuch as ethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's intravenousvehicles include fluid and nutrient replenishers, electrolytereplenishers (such as those based on Ringer's dextrose), and the like.Preservatives and other additives can also be present such as, forexample, antimicrobials, anti-oxidants, chelating agents, growth factorsand inert gases and the like.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations can contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation can bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds can have limited solubility in water and therefore canrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions can be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions disclosed herein can additionally include components toprovide sustained release and/or comfort. Such components include highmolecular weight, anionic mucomimetic polymers, gelling polysaccharides,and finely-divided drug carrier substrates. These components arediscussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841;5,212,162; and 4,861,760. The entire contents of these patents areincorporated herein by reference in their entirety for all purposes.

By the present, there are provided methods for ameliorating woundhealing and for mediating tissue repair (including but not limited totreatment of peripheral and coronary vascular disease). According tothese methods, a subject having a wound or in need of tissue repair, istreated at the site of the wound or damaged tissue or treatedsystemically, with a compound disclosed herein in the form of a freecompound or a pharmaceutically-acceptable prodrug, metabolite, analogue,derivative, solvate or salt.

Generally, the terms “treating”, “treatment” and the like are usedherein to mean affecting a subject, tissue or cell to obtain a desiredpharmacologic and/or physiologic effect. The effect can be prophylacticin terms of completely or partially preventing a disease or disorder orsign or symptom thereof, and/or can be therapeutic in terms of a partialor complete cure for a disorder and/or adverse effect attributable toit. “Treating” as used herein covers any treatment of, or prevention ofa disease or disorder in a vertebrate, a mammal, particularly a human,and includes: (a) preventing the disease or disorder from occurring in asubject that can be predisposed to the disease or disorder, but has notyet been diagnosed as having it; (b) inhibiting the disease or disorder,i.e., arresting its development; or (c) relieving or ameliorating thedisease or disorder, i.e., cause regression of the disease or disorder.

There are provided various pharmaceutical compositions useful forameliorating certain diseases and disorders. The pharmaceuticalcompositions according to one embodiment are prepared by formulating acompound disclosed herein in the form of a free compound or apharmaceutically-acceptable pro-drug, metabolite, analogue, derivative,solvate or salt, either alone or together with other pharmaceuticalagents, suitable for administration to a subject using carriers,excipients and additives or auxiliaries. Frequently used carriers orauxiliaries include magnesium carbonate, titanium dioxide, lactose,mannitol and other sugars, talc, milk protein, gelatin, starch,vitamins, cellulose and its derivatives, animal and vegetable oils,polyethylene glycols and solvents, such as sterile water, alcohols,glycerol and polyhydric alcohols. Intravenous vehicles include fluid andnutrient replenishers.

Preservatives include antimicrobial, anti-oxidants, chelating agents andinert gases. Other pharmaceutically acceptable carriers include aqueoussolutions, non-toxic excipients, including salts, preservatives, buffersand the like, as described, for instance, in Remington's PharmaceuticalSciences, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487(1975) and The National Formulary XIV, 14th ed. Washington: AmericanPharmaceutical Association (1975), the contents of which are herebyincorporated by reference. The pH and exact concentration of the variouscomponents of the pharmaceutical composition are adjusted according toroutine skills in the art. See e.g., Goodman and Gilman (eds.), 1990,THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

The pharmaceutical compositions are preferably prepared and administeredin dose units. Solid dose units are tablets, capsules and suppositories.For treatment of a subject, depending on activity of the compound,manner of administration, nature and severity of the disease ordisorder, age and body weight of the subject, different daily doses canbe used.

Under certain circumstances, however, higher or lower daily doses can beappropriate. The administration of the daily dose can be carried outboth by single administration in the form of an individual dose unit orelse several smaller dose units and also by multiple administrations ofsubdivided doses at specific intervals.

The pharmaceutical compositions contemplated herein can be administeredlocally or systemically in a therapeutically effective dose. Amountseffective for this use will, of course, depend on the severity of thedisease or disorder and the weight and general state of the subject.Typically, dosages used in vitro can provide useful guidance in theamounts useful for in situ administration of the pharmaceuticalcomposition, and animal models can be used to determine effectivedosages for treatment of particular disorders.

Various considerations are described, e. g., in Langer, 1990, Science,249: 1527; Goodman and Gilman's (eds.), 1990, Id., each of which isherein incorporated by reference and for all purposes. Dosages forparenteral administration of active pharmaceutical agents can beconverted into corresponding dosages for oral administration bymultiplying parenteral dosages by appropriate conversion factors. As togeneral applications, the parenteral dosage in mg/mL times 1.8=thecorresponding oral dosage in milligrams (“mg”). As to oncologyapplications, the parenteral dosage in mg/mL times 1.6=the correspondingoral dosage in mg. An average adult weighs about 70 kg. See e.g.,Miller-Keane, 1992, ENCYCLOPEDIA & DICTIONARY OF MEDICINE, NURSING &ALLIED HEALTH, 5th Ed., (W. B. Saunders Co.), pp. 1708 and 1651.

The method by which the compound disclosed herein can be administeredfor oral use would be, for example, in a hard gelatin capsule whereinthe active ingredient is mixed with an inert solid diluent, or softgelatin capsule, wherein the active ingredient is mixed with aco-solvent mixture, such as PEG 400 containing Tween-20. A compounddisclosed herein can also be administered in the form of a sterileinjectable aqueous or oleaginous solution or suspension. The compoundcan generally be administered intravenously or as an oral dose of 0.1 μgto 20 mg/kg given, for example, every 3-12 hours.

Formulations for oral use can be in the form of hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin. They can alsobe in the form of soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, such as peanut oil, liquid paraffinor olive oil.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspension. Suchexcipients can be (1) suspending agent such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2)dispersing or wetting agents which can be (a) naturally occurringphosphatide such as lecithin; (b) a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate; (c) acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethylenoxycetanol; (d) a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions can be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension can beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation can also a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

A compound disclosed herein can also be administered in the form ofophthalmic compositions applied topically to the eye, preferably in theform of eye drops. A compound disclosed herein can also be administeredin the form of intravitreal injection.

A compound disclosed herein can also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient that is solid at ordinary temperature but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycols.

The compounds disclosed herein as used in the methods disclosed hereincan also be administered in the form of liposome delivery systems, suchas small unilamellar vesicles, large unilamellar vesicles, andmultilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds disclosed herein, are employed.

In addition, some of the compounds disclosed herein can form solvateswith water or common organic solvents. Such solvates are encompassedwithin the scope of the methods contemplated herein.

B. Effective Dosages

Pharmaceutical compositions provided herein include compositions whereinthe active ingredient is contained in a therapeutically effectiveamount, i.e., in an amount effective to achieve its intended purpose.The actual amount effective for a particular application will depend,inter alia, on the condition being treated.

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated (e.g., the disease responsive to inhibition ofthrombin and/or KLKB1 and/or KLK1); presence of other diseases or otherhealth-related problems; kind of concurrent treatment; and complicationsfrom any disease or treatment regimen. Other therapeutic regimens oragents can be used in conjunction with the methods and compoundsdisclosed herein.

For any compound described herein, the therapeutically effective amountcan be initially determined from a variety of techniques known in theart, e.g., biochemical characterization of inhibition of enzyme(thrombin, KLKB1, or KLK1), cell culture assays, and the like. Targetconcentrations will be those concentrations of active compound(s) thatare capable of decreasing enzymatic activity as measured, for example,using the methods described.

Therapeutically effective amounts for use in humans can be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring enzymatic inhibitionand adjusting the dosage upwards or downwards, as described above.

Dosages can be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the methods disclosed herein, should be sufficient to affecta beneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side effects. Generally, treatment is initiated with smallerdosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. In some embodiments of amethod disclosed herein, the dosage range is 0.001% to 10% w/v. In someembodiments, the dosage range is 0.1% to 5% w/v.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration, and the toxicity profile of the selected agent.

Accordingly, in some embodiments, dosage levels of the compoundsdisclosed herein as used in the present methods are of the order ofe.g., about 0.1 mg to about 1 mg, about 1 mg to about 10 mg, about 0.5mg to about 20 mg per kilogram body weight, an average adult weighing 70kilograms, with a preferred dosage range between about 0.1 mg to about20 mg per kilogram body weight per day (from about 7.0 mg to about 1.4gm per patient per day). The amount of the compound disclosed hereinthat can be combined with the carrier materials to produce a singledosage will vary depending upon the host treated and the particular modeof administration. For example, a formulation intended for oraladministration to humans can contain about 5 μg to 1 g of a compounddisclosed herein with an appropriate and convenient amount of carriermaterial that can vary from about 5 to 95 percent of the totalcomposition. Dosage unit forms will generally contain between from about0.1 mg to 500 mg of a compound disclosed herein.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

C. Toxicity

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from in vitro assays, cell cultureassays and/or animal studies can be used in formulating a range ofdosages for use in humans. The dosage of such compounds preferably lieswithin a range of plasma concentrations that include the ED₅₀ withlittle or no toxicity. The dosage can vary within this range dependingupon the dosage form employed and the route of administration utilized.See, e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,Ch. 1, p. 1, 1975. The exact formulation, route of administration, anddosage can be chosen by the individual practitioner in view of thepatient's condition and the particular method in which the compound isused. For in vitro formulations, the exact formulation and dosage can bechosen by the individual practitioner in view of the patient's conditionand the particular method in which the compound is used.

Pharmacokinetics in Mice

In order to test compound exposure in animals, pharmacokinetics in miceis measured. Each compound is administered intravenously (i.v.) as asingle dose via tail vein or orally (p.o.) as a single dose via gastricgavage to male CD-1 mice of nominal weights between 20 g and 26 g.Nominal doses are 1 mg/kg and 5 mg/kg for i.v. and p.o., respectively.In some examples (dose type A), both p.o. and i.v. doses are prepared bydissolving the test compound in 5% dimethyl acetamide and diluted intetraethylene glycol for a final concentration of 0.25 mg/mL. In otherexamples (dose type B), i.v. doses are prepared by dissolving testcompounds in 20% dimethyl acetamide, 40% polyethylene glycol 300 and 40%phosphate buffered saline, and p.o. doses are prepared by dissolvingtest compounds in carboxymethyl cellulose suspension (1% by weight) inwater and 2.5% dimethyl acetamide.

Animals are housed in standard holding cages with food and wateravailable ad libitum except for animals used for p.o. dosing which arefasted overnight prior to dosing. Samples are taken in triplicate viacardiac puncture at times prior to dosing and at 0.083 (i.v. only),0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma isobtained by centrifuge and stored frozen until analyzed by LC-MS/MSusing a Shimadzu VP System HPLC coupled to a Applied Biosystems MDSSCIEX API 3000 triple quadrapole MS. Assay results are calibrated usingreference samples prepared in a range between 1.5 and 5000 ng/mL.

Pharmacokinetic parameters are calculated from mean concentration valuesusing a non-compartmental analysis as described in the following and asapparent to those of ordinary skill in the art. Half-lives (t_(1/2)) andelimination rate constants (λ) are determined by log linear regressionusing equal weighting on the last three finite sample time points.Concentration at time zero (C₀) for the i.v. data is established by theextrapolation of log linear regression using equal weighting on thefirst three sample time points. Area under the curve (AUC) values arecalculated using linear trapezoidal integration. Systemic clearance (CL)is calculated as the ratio of dosage and AUC. The apparent volume ofdistribution (V_(d)) is calculated as the ratio of CL and λ. Percentoral bioavailability (% F) is determined from the ratio of i.v. and p.o.AUC values weighted by dosage

Having described the invention in detail, it will be apparent thatmodifications, variations, and equivalent embodiments are possiblewithout departing the scope of the invention defined in the appendedclaims. Furthermore, it should be appreciated that all examples in thepresent disclosure are provided as non-limiting examples.

EXAMPLES

The following non-limiting examples are provided to further illustrateembodiments of the invention disclosed herein. It should be appreciatedby those of skill in the art that the techniques disclosed in theexamples that follow represent approaches that have been found tofunction well in the practice of the invention, and thus can beconsidered to constitute examples of modes for its practice. However,those of skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

General Scheme I. A synthetic scheme useful for synthesis of compoundsdescribed herein is disclosed in General Scheme I following, wherein theterms “R¹”, “R²”, “R³”, “R⁴” are as defined above, “R^(m)” and “R^(n)”are substituted or unsubstituted alkyl, and “R^(3′)” is a radicaldefined as the linkage of a methylene group attached to the radical “R³”as defined above.

General Scheme II. Further, we describe General Scheme II, syntheticallysimilar to General Scheme I, useful for the introduction of functionalgroups R³L³, wherein the terms “R¹”, “R²”, “R³”, “R⁴”, “R^(m)” and“R^(n)” are as defined above, and “R^(3′)” is a radical defined as thelinkage of a methylene group attached to the radical “R³”, as definedabove.

Example 1—Preparation of Intermediate 1

The synthesis of Intermediate 1 followed General Procedure 1 following.

General Procedure 1

To a solution of 2-hydroxynicotinic acid (50.0 g, 0.359 moles, 1.0 eq.)in dichloromethane (500 mL) at 0° C. was added thionyl chloride (133.6mL, 1.8 moles, 5.0 eq.) dropwise. After 30 min tetrahydrofuran (500 mL)was added and the reaction stirred for 14-15 hours at ambienttemperature. The reaction mixture was cooled to 0° C., to it was addedmethanol (150 mL) dropwise, and the mixture was stirred for a further 30min at room temperature. The reaction mixture was concentrated underreduced pressure to obtain a solid, which was then neutralized withaqueous sodium bicarbonate (pH 7-8), and again concentrated to obtainsolid product. The solid was dissolved in methanol, filtered, and thefiltrate concentrated to give desired product 45.0 g, (yield; 81.8%) m/z153.99 [M+H]⁺ ¹H NMR (DMSO-d6, 400 MHz) δ 8.051-074 (1H, q), 7.661-7.682(1H, q), 6.259-6.292 (1H, m), 3.734 (3H, s) ppm.

Example 2—Preparation of Intermediate 2

The synthesis of Intermediate 2 followed the procedure of GeneralProcedure 2 following.

General Procedure 2

To a cold (−78° C.) solution of acetonitrile (8.18 mL, 0.156 moles, 1.2eq.) in tetrahydrofuran (300 mL) was added n-BuLi (2.5M in Hexane; 62.68mL, 0.156 moles, 1.2 eq) dropwise over a period of 60 min. Afteraddition, the reaction was stirred for another 60 min, then to it addedmethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (Intermediate 1, 20.0 g,130 mmol, 1.0 eq) portionwise to reaction mixture and maintained −78° C.for 3 hrs. The reaction was quenched with water and washed with ethylacetate. The aqueous layer was evaporated to obtain crude product, whichwas suspended in methanol and stirred for 30 min at room temperature.The solid was filtered through suction and dried over high vacuum toafford Intermediate 2 (11.5 g, 54%).

Example 3—Preparation of Compound 1

The synthesis of Compound 1 followed the procedure of General Procedure3 following.

General Procedure 3

To a solution of Intermediate 2 (20.0 g, 0.123 moles, 1.0 eq) inisopropanol (600 mL) and acetic acid (22.2 mL) was added hydrazinemonohydrate (7.40 mL, 0.148 moles, 1.2 eq) dropwise and the reaction washeated at 85° C. for 4-5 Hrs. After cooling, the reaction mixture wasconcentrated to give crude product, which was purified by columnchromatography using neutral silica gel (60-120 mesh), eluting with10-25% methanol in dichloromethane as gradient to give the desiredproduct Compound 1 13.25 g (yield—61%) m/z 177.06 [M+H]+ 1H NMR(DMSO-d6, 400 MHz) δ 11.831 (1H, s), 7.857-7.879 (1H, q), 7.383-7.403(1H, q), 6.303-6.336 (1H, m), 6.048 (1H, s) 4.633 (2H, s) ppm.

Example 4—Preparation of Compound 2

The synthesis of Compound 2 followed the procedure of General Procedure4 following.

General Procedure 4

To a solution of Compound 1 in dimethylformamide (100 mL) at 10-15° C.was added acetic acid (11.2 mL) dropwise, followed by5-chlorothiophene-2-carbaldehyde (9.15 g, 0.0624 moles, 1.1 eq) addedportionwise. The reaction was stirred for 30-45 min at room temperature.Sodium cyanoborohydride (5.35 g, 0.0851 moles, 1.5 eq.) was addedportionwise over a period of 45 min and reaction was stirred for 2hours. After completion of reaction, the mixture was poured into icecold water under stirring and the product was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to obtain crude product, which waspurified by column chromatography using neutral silica gel and productwas eluted with 10-12% methanol in dichloromethane as mobile phase toyield pure desired product Compound 2 (7.3 g, yield: 42.7%) m/z [M+H]+307.10 1H NMR (DMSO-d6, 400 MHz) δ 12.034 (1H, s), 11.815 (1H, s),7.869-7.882 (1H, q), 7.404-7.415 (1H, d), 6.922-6.931 (1H, d),6.862-6.871 (1H, d), 6.314-6.331 (1H, d), 6.117 (1H, s), 5.867-5.898(1H, t), 4.348-4.363 (2H, d) ppm.

Example 5—Preparation of Compound 3

The synthesis of Compound 3 followed the procedure of General Procedure5 following.

General Procedure 5

To a cooled (0° C.) solution of Compound 2 in triethylamine (2.98 mL,0.0215 moles, 3.0 eq.) and dichloromethane (40 mL) was added pivaloylchloride (0.776 g, 0.00647 moles, 0.9 eq) dropwise over a period of 30minutes. The reaction was stirred for 2-3 hours by maintaining thetemperature below 10° C. After completion, the reaction was diluted withice cold water under stirring and the product was extracted withdichloromethane. The organic phase was dried over sodium sulfate andconcentrated under reduced pressure. The resultant crude product waspurified by column chromatography using neutral silica gel, eluting with5-8% methanol in dichloromethane to furnish pure desired product(Compound 3, 0.76 g, yield: 43.6%) m/z [M+H]⁺ 391.24 1H NMR (DMSO-d6,400 MHz) δ 11.250 (1H, s), 8.086-8.109 (1H, q), 7.731-7.761 (1H, t),7.484 (1H, s), 6.974-6.984 (1H, d), 6.934-6.944 (1H, d), 6.317-6.350(1H, t), 6.213 (1H, s), 4.471-4.486 (2H, d), 1.47 (9H, s) ppm.

Example 6—Preparation of Compound 4

The synthesis of Compound 4 followed the procedure of General Procedure6 following.

General Procedure 6

To a solution of furan-3-carboxylic acid (0.338 g, 0.00301 moles, 1.2eq) in dimethylformamide (5.0 mL) was added EDCI.HCl (0.724 g, 0.00337moles, 1.5 eq), DIEA (0.811 g, 0.00629 moles, 2.5 eq) and finally HOBt(0.074 g, 0.00048 moles, 0.5 eq). The reaction mixture was stirred atroom temperature for 30 min, followed by the addition of Compound 2(0.770 g, 0.00251 moles, 1.0 eq). The mixture was stirred at 14 hours atroom temperature. After checking that the reaction had reachedcompletion by LC-MS, the mixture was poured into ice cold water understirring. The product was extracted with ethyl acetate. The organicphase was dried over sodium sulfate, concentrated under reduced pressureand purified by column chromatography using neutral silica gel (60-120mesh), eluting with 15-25% ethyl acetate in n-hexane as gradient to givepure desired Compound 4 (0.45 g, yield: 45%) m/z [M+H]+ 401.84 1H NMR(DMSO-d6, 400 MHz) δ 11.923 (1H, s), 9.024-9.029 (1H, q), 8.274-8.297(1H, q), 7.888-7.893 (1H, d), 7.833-7.884 (1H, q), 7.500-7.512 (1H, d),7.085-7.091 (1H, q), 6.965-6.990 (2H, q), 6.313-6.347 (2H, t), 5.771(1H, s), 4.445-4.560 (1H, d) ppm.

Example 7—Preparation of Compound 5

The synthesis of Compound 5 followed the procedure of General Procedure7 following.

General Procedure 7

To a solution of Compound 4 (0.150 g, 0.375 mmoles, 1.0 eq) in DMF (5.0mL) was added anhydrous potassium carbonate (0.129 g, 0.937 mmoles, 2.5eq) and then stirred for 30 minutes at room temperature.2-(Chloromethyl)thiophene (0.059 g, 0.45 mmoles, 1.2 eq) was added tothe reaction mixture and the reaction stirred for a further 2-3 hours atroom temperature. The mixture was monitored by TLC and LCMS. Aftercompletion of reaction, the reaction mixture was poured into ice coldwater under stirring and extracted with ethyl acetate. The organic phasewas dried over sodium sulfate, concentrated under reduced pressure andpurified by column chromatography using neutral silica gel. The productwas eluted with 1-5% ethyl acetate as gradient in n-hexane to furnishCompound 5 (0.036 g, yield—19.3%) m/z [M+H]+ 497.23. 1H NMR (DMSO-d6,400 MHz) δ 9.020 (1H, s), 8.274-8.297 (1H, dd), 7.960-7.981 (1H, dd),7.885-7.893 (1H, t), 7.833-7.864 (1H, t), 7.519-7.539 (1H, dd),7.430-7.434 (1H, d), 7.117-7.133 (1H, dd), 7.087-7.091 (1H, d),6.975-6.987 (1H, t), 6.380-6.427 (1H, t), 6.435 (1H, s), 5.189 (2H, s),4.550-4.565 (2H, d) ppm.

Example 8—Preparation of Compound 6

The synthesis of Compound 6 followed the procedure of General Procedure8 following.

General Procedure 8

To a solution of Compound 4 (0.150 g, 0.375 mmoles, 1.0 eq.) in DMF (5.0mL) was added cesium carbonate (0.304 g, 0.937 mmoles, 2.5 eq.). Thereaction mixture was stirred for 30 min at room temperature, followed bythe addition of 4-(chloromethyl)pyridine hydrochloride (0.073 g, 0.45mmoles, 1.2 eq). The reaction was stirred for 3-4 hours at 70° C. Thereaction was monitored by TLC and LCMS. After completion of thereaction, the mixture was poured into ice cold water under stirring andextracted into ethyl acetate. The organic phase was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using neutral silica gel,eluting with 40-55% ethyl acetate as gradient in n-hexane to furnishCompound 6 (0.032 g, yield: 17.4%) m/z [M+H]+ 491.95. 1H NMR (DMSO-d6,400 MHz) δ 9.030 (1H, s), 8.541-8.526 (2H, d), 8.379-8.356 (1H, dd),8.020-7.999 (1H, dd), 7.893-7.836 (2H, m), 7.210-7.195 (2H, d),7.093-7.089 (1H, d), 6.968-6.948 (2H, t), 6.498-6.463 (1H, t), 6.294(1H, s), 5.255 (2H, s), 4.542-4.526 (2H, d) ppm.

Example 9—Preparation of Intermediate 3

The synthesis of Intermediate 3 followed General Procedure 1 following.

Acetyl Chloride (200 mL) was added slowly to ethanol (800 mL) at roomtemperature. The clear solution was stirred for 10 minutes and then4-hydroxynicotinic acid (50.0 g, 0.359 moles, 1.0 eq.) was added assolid. The reaction mixture was heated at reflux for overnight (12 hr).After completion, reaction mixture was concentrated under reducedpressure. The residue was diluted with dichloromethane (300 mL×3) andwater (300 mL). The layers were neutralized by NaHCO₃. The organic layerwas separated and the aqueous layer was extracted further withdichloromethane (300 mL×2). The combined organic layer was dried oversodium sulfate and concentrated to afford the desired product. (5.4 g,yield—90.00%). m/z [M+H]+ 167.8. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.529-7.512(1H, d), 6.814 (1H, s), 6.505-6.525 (1H, dd), 4.325-4.272 (2H, q),1.323-1.286 (3H, t) ppm.

Example 10—Preparation of Intermediate 4

The synthesis of Intermediate 4 followed General Procedure 2 following.

Acetonitrile (8.18 mL, 0.156 mol, 1.2 eq) was added in tetrahydrofuran(300 mL) and was then cooled to −78° C. ^(n)BuLi (2.5M in hexane, 62.68mL, 0.156 moles, 1.2 eq) was added dropwise over a period of 60 minutesand the reaction mixture was stirred further for 60 minutes.Intermediate 3 (20.0 g, 0.13 mol, 1.0 eq) was added portionwise to thereaction mixture at −78° C. and maintained for 3 hrs. After completion,the reaction was quenched with saturated ammonium chloride solution andwashed with ethyl acetate. The aqueous layer was evaporated to obtaincrude product, which was suspended in methanol and stirred for 30minutes at room temperature. The solid was suction-filtered and driedunder high vacuum to obtain desired product. (11.5 g, yield—58%). m/z[M+H]+ 163.05 ¹H NMR (CD₃CN, 400 MHz) δ 9.88 (1H, bs), 7.40-7.38 (1H,d), 6.84 (1H, s), 6.50-6.48 (1H, dd), 4.27 (2H, s) ppm.

Example 11—Preparation of Compound 7

The synthesis of Compound 7 followed the procedure of General Procedure3 following.

Intermediate 4 (20.0 g, 0.123 mol, 1.0 eq) was added to a mixture ofisopropanol (600 mL) and acetic acid (22.2 mL). To this was addedhydrazine monohydrate (7.40 mL, 0.148 moles, 1.2 eq) dropwise. Thereaction mixture was stirred at 85° C. for 4-5 hours. After completion,the reaction mixture was concentrated to give crude product, which waspurified by column chromatography using neutral silica gel (60-120mesh). The product was eluted with 10-15% methanol in dichloromethane asgradient to give desired product. (13.25 g, yield—61%). m/z [M+H]+176.9. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.492 (2H, bs), 7.336-7.318 (1H, d),6.529-6.515 (2H, d), 5.775 (1H, s), 4.995 (2H, s) ppm.

Example 12—Preparation of Compound 8

The synthesis of Compound 8 followed the procedure of General Procedure4 following.

Compound 7 (5.0 g, 28.4 mol, 1.0 eq) was dissolved in methanol (200 mL)at 10-15° C. and to it was added acetic acid (1.7 mL) dropwise. To thissolution was added 5-chlorothiophene-2-carbaldehyde (6.22 g, 42.6 mmol,1.5 eq) dropwise. The reaction was stirred for 30-45 minutes at roomtemperature. Sodium cyanoborohydride (3.52 g, 56.8 mmol, 2.0 eq) wasadded portionwise over a period of 45 minutes and reaction was stirredfor 2 hours. After completion, the reaction mixture was poured intoice-cold water (200 mL) under stirring and the product was extractedwith ethyl acetate (200 mL×3). The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by column chromatography using neutral silica gel eluting with10-12% methanol in dichloromethane as mobile phase. (6.9 g, yield—79.3%)m/z [M+H]+ 307.00. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.356 (1H, s), 11.475(1H, s), 7.370 (1H, s), 6.944-6.936 (2H, d), 6.576-6.487 (2H, m), 6.024(2H, s), 4.360-4.344 (2H, d) ppm.

Example 13—Preparation of Compound 9

The synthesis of Compound 9 followed the procedure of General Procedure6 following.

Furan-3-carboxylic acid (0.549 g, 4.9 mmol, 1.5 eq) was dissolved indimethylformamide (40 mL). EDCI.HCl (0.94 g, 4.9 mmol, 1.5 eq) and DIPEA(0.67 ml, 1.2 eq) were added to the reaction mixture and stirred at 10°C. for 30 minutes. Compound 8 (1.0 g, 3.27 mmol, 1.0 eq) and HOBt (0.088g, 0.65 mmol, 0.2 eq) were added to the reaction mixture and stirred for15 hours at room temperature. The reaction was monitored by LCMS. Aftercompletion, the reaction mixture was poured into ice cold water (150 mL)under stirring and extracted with ethyl acetate (150 mL×3). The organiclayer was dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography usingneutral silica gel, eluting with 60% ethyl acetate in n-nexane as mobilephase to give pure desired product (0.600 g, yield—45.8%). m/z [M+H]+401.30. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.661 (1H, s), 8.905 (1H, s),7.976-7.944 (1H, t), 7.910-7.901 (1H, s), 7.431-7.415 (1H, s),7.106-7.089 (2H, t), 6.981-6.971 (1H, d), 6.818 (1H, s), 6.761-6.742(1H, d), 6.240 (2H, s) ppm.

Example 14—Preparation of Compound 10

The synthesis of Compound 10 followed the procedure of General Procedure8 following.

Compound 9 (0.3 g, 0.75 mmol, 1.0 eq) was dissolved in DMF (40.0 mL) andanhydrous cesium carbonate (0.61 g, 1.87 mmol, 2.5 eq) was added. Thereaction was stirred for 30 minutes at room temperature. 2-(Bromoethyl)methyl ether (0.15 g, 1.12 mmol, 1.2 eq) was added to the reactionmixture and stirred overnight at room temperature. The reaction wasmonitored by TLC and LCMS. After completion the reaction mixture waspoured into ice cold water (80 mL) under stirring and the product wasextracted with ethyl acetate (80 mL×3). The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using silica gel (60-120mesh sized), eluting with 30-40% Ethyl acetate as gradient in n-Hexaneas mobile phase to give pure desired product. (0.100 g, yield—29.06%).m/z [M+H]+ 459.37. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.933 (1H, s),7.972-7.939 (1H, t), 7.902 (1H, s), 7.676-7.658 (1H, d), 7.104-7.092(1H, dd), 6.978-6.968 (2H, m), 6.885 (1H, s), 6.810-6.793 (1H, d), 6.244(1H, s), 4.555-4.539 (2H, t), 4.100-4.074 (2H, t), 3.602-3.576 (2H, t),3.293 (3H, s) ppm.

Example 15—Preparation of Compound 11

The synthesis of Compound 11 followed the procedure of General Procedure8 following.

Compound 9 (0.3 g, 0.75 mmol, 1.0 eq) was dissolved in DMF (25.0 mL),anhydrous cesium carbonate (0.61 g, 1.87 mmol, 2.5 eq) was added and thereaction was stirred for 30 minutes at room temperature. To this wasadded 2-chloro-1-morpholinoethan-1-one (0.184 g, 1.12 mmoles, 1.2 eq.)and the reaction mixture was stirred overnight at room temperature. Thereaction was monitored by TLC and LCMS. After completion, the reactionmass was poured into ice cold water (80 mL) under stirring and theproduct was extracted with ethyl acetate (100 mL×3). The organic layerwas dried over sodium sulphate and concentrated under reduced pressureto obtain a crude product, which was purified by column chromatographyusing silica gel (60-120 mesh sized) and eluting with 70-80% ethylacetate as gradient in n-hexane as mobile phase. (0.115 g,yield—29.04%). m/z [M+H]+ 528.06. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.950 (1H,s), 7.951-7.983 (1H, t), 7.607-7.625 (1H, d), 7.103-7.113 (2H, t),6.969-6.978 (1H, d), 6.900 (1H, s), 6.831-6.848 (1H, d), 6.273 (1H, s),4.864 (2H, s), 4.541-4.556 (2H, d), 3.662 (2H, s), 3.555-3.593 (4H, d),3.458 (2H, s) ppm.

Example 16—Preparation of Compound 12

The synthesis of Compound 12 followed the procedure of General Procedure8 following.

Compound 9 (0.3 g, 0.75 mmol, 1.0 eq) was dissolved in DMF (25.0 mL) andanhydrous cesium carbonate 0.610 g (1.87 mmoles, 2.5 eq.) was added. Thereaction was stirred for 30 minutes at room temperature.2-Chloromethylpyridine hydrochloride (0.185 g, 1.13 mmol, 1.2 eq) wasadded to the reaction mixture and the reaction mixture was stirredovernight at room temperature. The reaction was monitored by TLC andLCMS. After completion the reaction mixture was poured into ice coldwater (80 mL) under stirring and extracted with ethyl acetate (100mL×3). The organic phase was dried over sodium sulfate, concentratedunder reduced pressure and purified by column chromatography usingsilica gel (100-200 mesh sized). The product was eluted with 60-70%Ethyl acetate as gradient in n-Hexane as mobile phase to give puredesired product. (0.100 g, yield—27.10%) m/z [M+H]+ 492.43. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.949 (1H, s), 8.505-8.514 (1H, dd), 7.971 (1H, d),7.857-7.905 (2H, m), 7.783 (1H, t), 7.096-7.318 (2H, m), 7.096 (2H, s),6.967-6.976 (1H, d), 6.881-6.918 (2H, m), 6.270 (1H, s), 5.233 (2H, s),4.541-4.556 (2H, d) ppm.

Example 17—Preparation of Compound 13

The synthesis of Compound 13 followed the procedure of General Procedure6 following.

To a solution of pivalic acid (0.544 g, 5.44 mmol, 1.2 eq) in DMF (100mL) was added EDCI.HCl (1.045 g, 5.44 mmol, 1.2 eq) and DIPEA (0.93 ml,1.2 eq), and the mixture was stirred at 10° C. for 30 minutes. Aftercompletion, Compound 9 (2.0 g, 6.53 mmol, 1.0 eq.) and HOBt (0.199 g,1.307 mmol, 0.2 eq) were added, and the reaction mixture stirred for 15hours at room temperature. The reaction was monitored by LCMS. Aftercompletion, the reaction mixture was poured into ice cold water (300 mL)under stirring and the product was extracted with ethyl acetate (300mL×3). The organic phase was dried over sodium sulfate, concentratedunder reduced pressure, and chromatographed using neutral silica gel.The product was eluted with 60% ethyl acetate in n-hexane as mobilephase, to give pure desired product (1.56 g, yield—61.41%. m/z [M+H]+391.44. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.593 (1H, bs), 7.616-7.586 (1H, t),7.324-7.305 (1H, dd), 6.955-6.946 (1H, d), 6.879-6.870 (1H, d),6.731-6.689 (2H, m), 5.862 (1H, s), 4.527-4.509 (2H, t), 1.512 (9H, s)ppm.

Example 18—Preparation of Compound 14

The synthesis of Compound 14 followed the procedure of General Procedure8 following.

To a solution of Compound 13 (0.3 g, 0.769 mmol, 1.0 eq) in DMF (15.0mL) was added anhydrous cesium carbonate 0.624 g (1.92 mmol, 2.5 eq).The reaction was stirred for 30 minutes at room temperature.2-(Bromoethyl) methyl ether (0.16 g, 1.15 mmol, 1.5 eq) was added andthe reaction mixture stirred overnight at room temperature. The reactionwas monitored by TLC and LCMS. After completion the reaction mixture waspoured into ice cold water (80 mL) under stirring, and extracted withethyl acetate (80 mL×3). The organic phase was dried over sodium sulfateand concentrated under reduced pressure. The crude product was purifiedby column chromatography using silica gel (60-120 mesh sized), elutingwith 30-40% ethyl acetate in n-hexane as mobile phase to give puredesired product. (0.090 g, yield—27.95%. m/z [M+H]+ 449.27. ¹H NMR(DMSO-d₆, 400 MHz) δ 7.874-7.843 (1H, t), 7.681-7.664 (1H, dd),7.082-7.074 (1H, d), 6.973-6.964 (1H, d), 6.816 (1H, s), 6.645-6.627(1H, d), 6.120 (1H, s), 4.488-4.473 (2H, t), 4.078-4.052 (2H, t),3.592-3.567 (2H, t), 3.244 (3H, s), 1.464 (9H, s) ppm.

Example 19—Preparation of Compound 15

The synthesis of Compound 15 followed the procedure of General Procedure8 following.

To a solution of Compound 13 (0.3 g, 0.512 mmol, 1.0 eq) in DMF (15.0mL) was added anhydrous cesium carbonate (0.333 g, 1.02 mmol, 2.5 eq).The reaction was stirred for 30 minutes at room temperature.2-Chloro-1-morpholinoethan-1-one (0.189 g, 0.615 mmol, 1.5 eq) was addedand the reaction mixture was stirred overnight at room temperature. Thereaction was monitored by TLC and LCMS. After completion the reactionmixture was poured into ice cold water (80 mL) under stirring andproduct was extracted with ethyl acetate (100 mL×3). The organic phasewas dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography using silica gel(60-120 mesh sized), eluting with 70-80% ethyl acetate in n-Hexane asmobile phase to give pure desired product. (0.075 g, yield—18.89%) m/z[M+H]+ 517.83. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.849-7.881 (1H, t),7.601-7.619 (1H, d), 7.080-7.089 (1H, d), 6.963-6.972 (1H, d), 6.826(1H, s), 6.654-6.676 (1H, t), 6.143 (1H, s), 4.846 (2H, s), 4.475-4.490(2H, d), 3.646-3.657 (2H, s), 3.452-3.590 (4H, d), 3.344 (2H, s), 1.470(9H, s) ppm.

Example 20—Preparation of Compound 16

The synthesis of Compound 16 followed the procedure of General Procedure8 following.

To a solution of Compound 13 (0.350 g, 0.769 mmol, 1.0 eq) in DMF (15.0mL) was added anhydrous cesium carbonate (0.499 g, 1.15 mmol, 2.5 eq).The reaction was stirred for 30 minutes at room temperature.2-(Chloromethyl)pyridine hydrochloride (0.189 g, 1.54 mmol, 1.5 eq) wasadded and the reaction stirred overnight at room temperature. Thereaction was monitored by TLC and LCMS. After completion the reactionmixture was poured into ice cold water (100 mL) under stirring andproduct was extracted with ethyl acetate (100 mL×3). The organic layerwas dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography using silica gel(100-200 mesh sized), eluting with 50% ethyl acetate in n-hexane to givepure desired product (0.075 g, yield—17.36%) m/z [M+H]+ 482.38. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.497-8.509 (1H, d), 7.856-7.888 (2H, m),7.752-7.795 (1H, t), 7.282-7.314 (1H, dd), 7.226-7.245 (1H, d),7.075-7.084 (1H, d), 6.961-6.971 (1H, d), 6.846-6.6.851 (1H, d),6.707-6.729 (1H, dd), 6.146 (1H, s), 5.212 (1H, s), 4.474-4.490 (2H, d),1.469 (9H, s) ppm.

Example 21—Preparation of Compound 17

The synthesis of Compound 17 followed the procedure of General Procedure6 following.

To a cold (10° C.) solution of thiophene-3-carboxylic acid (1 g, 7.84mmol, 1.2 eq) in DMF (40.0 mL) was added EDCI.HCl (1.5 g, 7.84 mmol, 1.2eq) and DIPEA (1.47 mL, 1.2 eq). The mixture was stirred at 10° C. for30 min. After completion, Compound 8 (2.0 g, 6.53 mmol, 1.0 eq) wasadded, followed by HOBt (0.239 g, 1.56 mmol, 0.2 eq), and the reactionmixture was then stirred for 15 hours at room temperature. The reactionwas monitored by LCMS. After completion, the reaction mixture was pouredinto ice cold water (300 mL) under stirring and extracted with ethylacetate (300 mL×3). The organic phase was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography using neutral silica gel, eluting with 80% ethyl acetatein n-hexane as mobile phase to give pure desired product (1.023 gm,yield—37.74%). m/z [M+H]+ 417.30. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.651(1H, bs), 9.002-8.992 (1H, s), 7.993-7.962 (1H, t), 7.834-7.818 (1H, m),7.706-7.686 (1H, d), 7.439-7.422 (1H, dd), 7.111-7.102 (1H, d),6.983-6.974 (1H, d), 6.814 (1H, s), 6.711-6.694 (1H, d), 6.244 (1H, s),4.561-4.546 (2H, t) ppm.

Example 22—Preparation of Compound 18

The synthesis of Compound 18 followed the procedure of General Procedure8 following.

To a solution of Compound 17 (0.3 g, 0.721 mmol, 1.0 eq) in DMF (25.0mL) was added anhydrous cesium carbonate (0.585 g, 1.80 mmol, 2.5 eq).The reaction was stirred for 30 minutes at room temperature.3-(Chloromethyl)pyridine hydrochloride (0.236 g, 1.44 mmol, 1.5 eq) wasadded and the reaction mixture was stirred overnight at roomtemperature. The reaction was monitored by TLC and LCMS. Aftercompletion the reaction mass was poured into ice cold water (100 mL)under stirring and extracted with ethyl acetate (100 mL×3). The organicphase was dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by preparative HPLC chromatography toyield Compound 18 (0.038 g, yield—10.4%). m/z [M+H]+ 508.83. ¹H NMR(DMSO-d₆, 400 MHz) δ 9.030-9.020 (1H, d), 8.614 (1H, s), 8.523-8.510(1H, d), 7.999-7.828 (2H, m), 7.824-7.812 (1H, m), 7.752-7.732 (1H, d),7.700-7.679 (1H, dd), 7.423-7.390 (1H, m), 7.104-7.094 (1H, m),6.974-6.938 (1H, dd), 6.934-6.836 (1H, d), 6.832-6.814 (1H, dd), 6.268(1H, s), 5.181 (2H, s), 4.555-4.539 (2H, t) ppm.

Example 23—Preparation of Compound 19

The synthesis of Compound 19 followed the procedure of General Procedure8 following.

To a solution of Compound 17 (0.3 g, 0.721 mmol, 1.0 eq) in DMF (25.0mL) was added anhydrous cesium carbonate (0.587 g, 1.80 mmol, 2.5 eq).The reaction was stirred for 30 minutes at room temperature.2-(Bromoethyl) methyl ether (0.150 g, 1.08 mmol, 1.2 eq) was added andthe reaction mixture stirred overnight at room temperature. The reactionwas monitored by TLC and LCMS. After completion the reaction mixture waspoured into ice cold water (80 mL) under stirring and extracted withethyl acetate (80 mL×3). The organic phase was dried over sodium sulfateand concentrated under reduced pressure. The resultant residue waspurified by column chromatography using silica gel (60-120 mesh sized),eluting with 30-40% ethyl acetate in n-hexane as mobile phase to givepure desired product. (0.090 g, yield—25.28%). m/z [M+H]+ 475.32. ¹H NMR(DMSO-d₆, 400 MHz) δ 9.035-9.025 (1H, d), 7.995-7.964 (1H, t),7.834-7.819 (1H, dd), 7.704-7.684 (2H, m), 7.111-7.102 (1H, d),6.982-6.972 (1H, dd), 6.885-6.881 (1H, d), 6.753-6.731 (1H, dd), 6.251(1H, s), 4.561-4.546 (2H, t), 4.097-4.071 (2H, t), 3.602-3.576 (2H, t),3.250 (3H, s) ppm.

Example 24—Preparation of Compound 20

The synthesis of Compound 20 followed the procedure of General Procedure8 following.

To a solution of Compound 17 (0.3 g, 0.721 mmol, 1.0 eq) in DMF (16.0mL) was added anhydrous cesium carbonate (0.587 g, 1.80 mmol, 2.5 eq).The reaction mixture was stirred for 30 minutes at room temperature.2-Chloro-1-morpholinoethan-1-one (0.176 g, 1.08 mmol, 1.2 eq) was addedand the reaction mixture was stirred overnight at room temperature. Thereaction was monitored by TLC and LCMS. After completion the reactionmixture was poured into ice cold water (100 mL) under stirring andextracted with ethyl acetate (100 mL×3). The organic phase was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography using silica gel (60-120 meshsized), eluting with 70-80% ethyl acetate in n-hexane as mobile phase togive pure desired product (0.085 g, yield—21.62%). m/z [M+H]+ 545.03. ¹HNMR (DMSO-d₆, 400 MHz) δ 9.036-9.044 (1H, t), 7.968-8.00 (1H, t),7.825-7.838 (1H, t), 7.686-7.707 (1H, m), 7.613-7.630 (1H, d),7.109-7.118 (1H, d), 6.972-6.981 (1H, d), 6.892-6.896 (1H, d),6.760-6.782 (1H, m), 6.276 (1H, s), 5.769 (1H, s), 4.861 (2H, s),4.549-4.565 (2H, d), 3.653-3.663 (2H, s), 3.555-3.596 (4, m),3.458-3.469 (2H, s) ppm.

Example 25—Preparation of Compound 21

The synthesis of Compound 21 followed the procedure of General Procedure8 following:

To a solution of Compound 17 (0.300 g, 0.721 mmol, 1.0 eq) in DMF (16.0mL) was added anhydrous cesium carbonate (0.587 g, 1.80 mmol, 2.5 eq).The reaction mixture was stirred for 30 minutes at room temperature.2-(Chloromethyl)pyridine hydrochloride (0.177 g, 1.08 mmole, 1.2 eq) wasadded and the reaction mixture was stirred overnight at roomtemperature. The reaction was monitored by TLC and LCMS. Aftercompletion the reaction mixture was poured into ice cold water (100 mL)under stirring and extracted with ethyl acetate (100 mL×3). The organicphase was dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography using silicagel (100-200 mesh sized), eluting with 70% ethyl acetate in n-hexane togive pure desired product (0.065 g, yield—17.75%) m/z [M+H]+ 508.62. ¹HNMR (DMSO-d₆, 400 MHz) δ 9.044 (1H, s), 9.037-9.040 (1H, s), 8.502-8.514(1H, d), 7.979-7.994 (1H, d), 7.801-7.880 (2H, m), 7.762-7.796 (1H, d),7.685-7.705 (1H, m), 7.285-7.314 (1H, t), 7.229-7.248 (1H, d),7.107-7.113, (1H, d), 6.955-6.979 (1H, t) 6.902-6.914 (1H, d),6.815-6.837 (1H, m), 6.261-6.275 (1H, d), 5.216-5.230 (2H, s),4.547-4.560 (2H, s) ppm.

Example 26—Preparation of Intermediate 5

The synthesis of Intermediate 5 followed General Procedure 1 following:

To a cold (0° C.) solution of5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100.0 g, 0.459 mol,1.0 eq) in dichloromethane (1 L) was added thionyl chloride (167.5 g,4.6 mol, 10.0 eq) dropwise. After 30 min tetrahydrofuran (1 L) was addedand the reaction allowed to stir for 14-15 hours at ambient temperature.The mixture was cooled back to 0° C. and to it was added methanol (500mL) dropwise. The mixture was stirred without cooling for a further 30minutes. After completion, the reaction mixture was concentrated underreduced pressure to obtain a solid residue, which was washed with hexaneand ethyl acetate and dried under reduced pressure to give desireproduct (98 g, yield—81.9%) m/z 232.02 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz)δ 12.43 (s, 1H), 8.08 (d, J=2.9 Hz, 1H), 7.99 (d, J=2.9 Hz, 1H), 3.75(s, 3H) ppm.

Example 27—Preparation of Intermediate 6

The synthesis of Intermediate 6 followed General Procedure 2 following:

Under an atmosphere of nitrogen, acetonitrile (12.01 g, 0.293 mol, 1.7eq) was added in tetrahydrofuran (600 mL) and the solution cooled to−78° C. A solution of BuLi (2.5M in hexane, 117 mL, 0.293 mol, 1.7 eq)was added dropwise over a period of 60 minutes and reaction was stirredfor another 60 minutes. Methyl5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (Intermediate 5, 40 g,0.172 mol, 1.0 eq) was added in portions to the reaction mixture at −78°C. and maintained for 3 hours, after which it was allowed to reach roomtemperature. The reaction mixture was direct evaporated and the residuewashed with hexane (200 mL×2), followed by 20% ethyl acetate in hexane(200 mL×2). The resultant solid was dried under reduced pressure to givedesired product (35 g; yield—84.33%) m/z 241.02 [M−H].

Example 28—Preparation of Compound 22

The synthesis of Compound 22 followed General Procedure 3 following:

3-(5-Bromo-2-oxo-1,2-dihydropyridin-3-yl)-3-oxopropanenitrile(Intermediate 6, 10.0 g (0.041 mol, 1.0 eq) and acetic acid (2.49 g,0.041 mol, 1.0 eq) were added to isopropanol (150 mL). To this was addedhydrazine monohydrate (3.11 mL, 0.062 mol, 1.5 eq) dropwise. Thereaction was stirred at 50-60° C. for 4-5 hours. The reaction wasmonitored by LC-MS, and after completion the reaction mixture wasconcentrated. The crude product was purified by column chromatographyusing neutral silica gel (60-120 mesh), eluting with 6-7% methanol indichloromethane to give desired product (6 g, yield—57.19%) m/z 255.07[M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 11.70 (s, 2H), 7.99 (d, J=2.7 Hz,1H), 7.67 (d, J=2.6 Hz, 1H), 6.14 (s, 1H), 4.77 (s, 2H) ppm.

Example 29—Preparation of Compound 23

The synthesis of Compound 23 followed General Procedure 4 following:

To a solution of 3-(5-amino-1H-pyrazol-3-yl)-5-bromopyridin-2(1H)-one(Compound 22, 5 g, 0.0196 mol, 1 eq) in methanol (50 mL) at 10-15° C.was added acetic acid (1.17 g, 0.0196 mol, 1 eq) dropwise, followed bythe portionwise addition of 5-chlorothiophene-2-carbaldehyde (2.86 g,0.0196 mol, 1 eq). The reaction was stirred for 4-5 hr at roomtemperature. Sodium cyanoborohydride (2.47 g, 0.0392 mol, 2 eq) wasadded portionwise at 0° C. over a period of 45 minutes, and the reactionwas stirred for 2 hours. The reaction mixture was monitored by LC-MS.After completion the volatiles were distilled off and the residue waspoured into ice cold water under stirring. The product was extractedwith 10% methanol in dichloromethane. The organic layer was dried oversodium sulfate, then concentrated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel, elutingwith 9% methanol in dichloromethane to give pure desired product (3.7 g,yield—62.7%) m/z [M+H]+ 387.11 ¹H NMR (DMSO-d₆, 400 MHz) δ 12.02 (m,2H), 8.01 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 6.93 (d, J=3.7 Hz, 1H), 6.87(d, J=3.7 Hz, 1H), 6.24 (s, 1H), 5.96 (s, 1H), 4.35 (d, J=6.3 Hz, 2H)ppm.

Example 30—Preparation of Intermediate 7

The synthesis of Intermediate 7 followed General Procedure 8 following.

General Procedure 8

To a round-bottomed flask charged with methyl5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (Intermediate 5, 50.0 g,0.2154 mol, 1.0 eq) at 0° C. under N₂ atmosphere was added POCl₃ (100mL) dropwise. After 30 minutes the reaction mixture was warmed to 80° C.and stirred for 12-15 hours. After completion of the reaction, thereaction mixture was cooled to room temperature and poured slowly intoice cold water. It was stirred for 30 min, at which point the productprecipitated out as a white solid. The solid product was filtered andvacuum dried to give desired Intermediate 7 (40.0 g, yield—94.15%). m/z252.12 [M+2]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 8.78 (d, J=2.5 Hz, 1H), 8.50(d, J=2.5 Hz, 1H), 3.89 (s, 3H) ppm.

Example 31—Preparation of Intermediate 8

The synthesis of Intermediate 8 followed General Procedure 9 following.

General Procedure 9

To cooled (0° C. under N₂ atmosphere) methanol (90 mL) was added sodiummetal (10.3 g, 0.449 mol, 3.75 eq) in small pieces. After 30 minutes aclear solution was observed. To this solution was added methyl5-bromo-2-chloronicotinate (Intermediate 7, 30.0 g, 0.119 mol, 1.0 eq)portionwise. After completion of addition, the reaction mixture wasallowed to attain room temperature and stirred for a further 2 hours.After completion of reaction, as monitored by LC-MS, the mixture wascooled to 0° C. To the mixture was added acetic acid, until the mixturereached pH 7, and then stirred at room temperature for a further 30minutes. The reaction mixture was poured into ice cold water understirring, and product was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate and concentrated under reducedpressure. The resultant residue was purified by column chromatographyusing neutral silica gel, eluting with 0-6% ethyl acetate in n-hexane asmobile phase to give pure desired product (methyl5-bromo-2-methoxynicotinate, Intermediate 8, 20.0 g, yield—67.86.7%) m/z[M+2]+ 246.17.10 ¹H NMR (DMSO-d₆, 400 MHz) δ 8.53 (d, J=2.6 Hz, 1H),8.27 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H) ppm.

Example 32—Preparation of Intermediate 9

The synthesis of Intermediate 9 followed General Procedure 2 following:

Under a nitrogen atmosphere, acetonitrile (5.7 g, 0.138 mol, 1.7 eq) wasadded to tetrahydrofuran (200 mL), and the solution cooled to −78° C. Tothis cold solution was added 2.5M ^(n)BuLi (in hexane) (55.2 mL, 0.138mol, 1.7 eq) dropwise over a period of 60 minutes and the reaction wasstirred for another 60 minutes. Methyl 5-bromo-2-methoxynicotinate(Intermediate 8, 20.0 g, 0.081 mol, 1.0 eq) was added portionwise to thereaction mixture at −78° C. and stirred for a further 3 hours. Thereaction was quenched with saturated ammonium chloride solution, andproduct was extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel, elutingwith 0-20% ethyl acetate in n-hexane to give pure desired product(3-(5-bromo-2-methoxypyridin-3-yl)-3-oxopropanenitrile, Intermediate 9,15.0 g (yield—86.83%) m/z [M+2]+ 257.12).

Example 33—Preparation of Compound 24

The synthesis of compound 24 followed General Procedure 3 following:

To a room temperature solution of3-(5-bromo-2-methoxypyridin-3-yl)-3-oxopropanenitrile (Intermediate 9,20.0 g, 0.0784 mol, 1.0 eq) in isopropanol (200 mL) and acetic acid (5.0mL) was added hydrazine monohydrate (5.0 mL, 0.078 mol, 1.0 eq)dropwise. The reaction was then stirred at 65° C. for 12 hours. Thereaction was monitored by LC-MS, and on completion it was concentratedunder reduced pressure, and then purified by column chromatography usingneutral silica gel (60-120 mesh). The crude product was eluted by using0-80% ethyl acetate in n-hexane to give desired product(3-(5-bromo-2-methoxypyridin-3-yl)-1H-pyrazol-5-amine, Compound 24, 15.0g, yield—71%) m/z [M+2]+ 269.18 ¹H NMR (DMSO-d₆, 400 MHz) δ 11.71 (s,1H), 8.25 (d, J=2.5 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 5.97 (s, 1H), 4.86(s, 2H), 3.94 (d, J=7.5 Hz, 3H) ppm.

Example 34—Preparation of Compound 25

The synthesis of compound 25 followed General Procedure 4 following:

To a solution of 3-(5-bromo-2-methoxypyridin-3-yl)-1H-pyrazol-5-amine,(Compound 24, 10.0 g, 0.037 mol, 1.0 eq) in methanol (150 mL) at 10-15°C. was added acetic acid (5.0 mL) dropwise. To this was added5-chlorothiophene-2-carbaldehyde (6.53 g, 0.044 mol, 1.2 eq)portionwise, and the reaction was stirred for a further 3-4 hours atroom temperature. Sodium cyanoborohydride (3.5 g, 0.055 mol, 1.5 eq) wasadded portionwise over a period of 45 minutes, and the reaction wasstirred for a further 12 hours. After completion, the reaction mixturewas poured into ice cold water under stirring, and extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated. The residue was purified by column chromatography usingneutral silica gel, eluting with 10-15% ethyl acetate in n-hexane toyield pure desired product (7.3 g, yield—47.2%) m/z [M+2]+ 401.26 ¹H NMR(DMSO-d₆, 400 MHz) δ 12.04 (s, 1H), 8.25 (t, J=5.1 Hz, 2H), 6.93 (s,1H), 6.88 (s, 1H), 6.16 (s, 1H), 5.96 (s, 1H), 4.37 (d, J=6.3 Hz, 2H),3.96 (s, 3H) ppm.

Example 35—Preparation of Intermediate 10

The synthesis of Intermediate 10 followed General Procedure 10following:

General Procedure 10

To a room temperature solution of 6-hydroxynicotinic acid (13.9 g, 0.1mol, 1.0 eq) in acetic acid (25 mL, 0.3 mol, 3.0 eq) was added bromine(7.6 mL, 0.05 mol, 0.5 eq) dropwise. The mixture was then stirred at 60°C. for 12 hours. After completion of reaction (starting materialconsumed as detected by LC-MS), the reaction mixture was poured intocold water. The white precipitate was filtered off and washed withsaturated sodium thiosulfate solution, and then dried under reducedpressure to give the desired product (20.0 g, yield—91%) m/z 220.11[M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 13.01 (s, 1H), 12.62 (s, 1H), 8.16(d, J=2.3 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H) ppm.

Example 36—Preparation of Intermediate 11

The synthesis of Intermediate 11 followed General Procedure 1 following:

To a cold (0° C.) solution of5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylic acid (Intermediate 10,20.0 g, 0.091 mol, 1.0 eq) in dichloromethane (200 mL) was added thionylchloride (32 g, 3.0 eq) dropwise. After 30 minutes, tetrahydrofuran (200mL) was added and the reaction allowed to stir for 14-15 hours atambient temperature. The reaction mixture was cooled back to 0° C. andto it was added methanol (100 mL) dropwise. At the completion ofaddition, the reaction was stirred for 30 min at room temperature. Aftercompletion of reaction (monitored by means of LC-MS), the reactionmixture was concentrated under reduced pressure to obtain a solid. Thiswas washed with hexane and ethyl acetate and then dried under reducedpressure to give the desired product (20.0 g, yield—82.3%) m/z 234.15[M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 12.74 (s, 1H), 8.18 (d, J=2.4 Hz,1H), 8.10 (d, J=2.4 Hz, 1H), 3.78 (s, 3H) ppm.

Example 37—Preparation of Intermediate 12

The synthesis of Intermediate 12 followed General Procedure 8 following.

To a round-bottomed flask containing phosphorus oxychloride (57 g, 0.37mol, 5.0 eq) was added methyl5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (Intermediate 11, 20.0g, 0.074 mol, 1.0 eq). The reaction was stirred at 70° C. for 4-5 hours.After the completion of reaction, the mixture was poured on to crushedice, and the precipitate was filtered off and neutralized usingsaturated sodium bicarbonate. The product was dried under reducedpressure to give desired product (Intermediate 12, 16 g, yield—85.5%)m/z 252.07 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 8.94 (d, J=2.0 Hz, 1H),8.53 (dd, J=7.5, 2.0 Hz, 1H), 3.99 (s, 3H) ppm.

Example 38—Preparation of Intermediate 13

The synthesis of Intermediate 13 followed General Procedure 11following:

General Procedure 11

To a cold (0° C.) solution of 3-(5-amino-1H-pyrazol-3-yl)pyridine-2(1H)-one (Intermediate 11, 9.0 g, 0.036 mol, 1 eq) in methanol(25 mL) was added sodium methoxide (25% in methanol, 15.5 mL, 0.072 mol,2 eq). The reaction was stirred for 2 hours at room temperature. Aftercompletion of reaction, the reaction mixture was evaporated underreduced pressure, and the residue was poured into ice cold water understirring. This mixture was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography usingneutral silica gel, eluting with 25-30% ethyl acetate in hexane to givepure desired product (7.5 g, yield—84.74%) m/z [M+H]+ 246.17 ¹H NMR(DMSO-d₆, 400 MHz) δ 8.73 (d, J=1.5 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H),4.02 (d, J=1.1 Hz, 3H), 3.86 (d, J=1.1 Hz, 3H) ppm.

Example 39—Preparation of Intermediate 14

The synthesis of Intermediate 14 followed General Procedure 2 following:

To a cooled solution (−78° C.) of acetonitrile (1.98 g, 0.048 mol, 1.7eq) in tetrahydrofuran (70 mL) was added ^(n)BuLi (2.5M in hexane, 19mL, 0.048 mol, 1.7 eq) dropwise over a period of 60 minutes. Thereaction was stirred thereafter for another 60 minutes. To this wasadded methyl 5-bromo-6-methoxynicotinate (Intermediate 13, 7 g, 0.027mol, 1.0 eq) portionwise, and the reaction mixture maintained at −78° C.for 3 hours. The reaction mixture was quenched with ammonium chloridesolution and extracted with ethyl acetate. The organic phase was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel, elutingwith 45-50% ethyl acetate in hexanes to give pure desired product (6 g,yield—82.75%) m/z [M+H]+ 255.21 ¹H NMR (DMSO-d₆, 400 MHz) δ 8.40 (d,J=1.9 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 3.91 (s, 3H), 3.17 (s, 2H) ppm.

Example 40—Preparation of Compound 26

The synthesis of compound 26 followed General Procedure 3 following:

To a room temperature solution of3-(5-bromo-6-methoxypyridin-3-yl)-3-oxopropanenitrile (Intermediate 14,6.0 g, 0.023 mol, 1.0 eq) in isopropanol (60 mL) and acetic acid (1.41g, 0.023 mol, 1.0 eq) was added hydrazine monohydrate (1.76 g, 0.035mol, 1.5 eq) dropwise. The reaction was stirred at 85° C. for 4-5 hours.After reaction completion, the mixture was concentrated. The residue waspurified by column chromatography using neutral silica gel (60-120mesh), eluting with 70-75% ethyl acetate in hexane give desired product(6 g, yield—95%) m/z 271.18 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 8.45 (d,J=2.1 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 5.74 (s, 1H), 5.17 (s, 2H), 3.94(s, 3H) ppm.

Example 41—Preparation of Compound 27

The synthesis of compound 27 followed General Procedure 4 following:

To a cold solution (10-15° C.) of3-(5-bromo-6-methoxypyridin-3-yl)-1H-pyrazol-5-amine (Compound 26, 6 g,0.023 mol, 1 eq) in methanol (60 mL) was added acetic acid (1.41 g,0.023 mol, 1 eq) dropwise. To this was then added5-chlorothiophene-2-carbaldehyde (3.43 g, 0.023 mol, 1 eq) portionwise,and the reaction then stirred for 2-3 hours at room temperature. Themixture was then cooled back to 0° C., sodium cyanoborohydride (2.96 g,0.047 mol, 2 eq) was then added portionwise over 45 minutes, and thereaction was stirred at room temperature for 2 hours. The reaction wasmonitored by LCMS. After completion the reaction mixture was evaporatedand the residue was poured into ice cold water under stirring. Theproduct was extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel elutingwith 50-55% ethyl acetate in hexanes to give pure desired product (6.2g, yield—65.95%) m/z [M+H]+ 401.26 ¹H NMR (DMSO-d₆, 400 MHz) δ 12.05 (s,1H), 8.48 (d, J=2.1 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 6.93 (d, J=3.7 Hz,1H), 6.90 (d, J=3.7 Hz, 1H), 6.07 (s, 1H), 5.97 (s, 1H), 4.36 (d, J=6.2Hz, 2H), 3.94 (s, 3H) ppm.

Example 42—Preparation of Intermediate 15

The synthesis of intermediate 15 followed General Procedure 12following:

General Procedure 12

Methyl 5-bromo-2-methoxynicotinate (Intermediate 8, 10 g, 0.040 mol, 1.0eq), morpholine (7.07 g, 0.081 mol, 2.0 eq) and Cs₂CO₃ (26.4 g, 0.081mol, 2.0 eq) were dissolved in dioxane (100 mL) at room temperature. Thereaction mixture was degassed using N₂ for 15 min. To the mixture wasthen added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos,1.1 g, 0.002 mol, 0.05 eq) and tris(dibenzylideneacetone)dipalladium(0)(Pd₂(dba)₃, 1.8 g, 0.002 mol, 0.05 eq) at room temperature. The reactionmixture was stirred at 90° C. for 15 h. After cooling, the reactionmixture was partitioned between EtOAc and water. The organic layer wascombined and dried over sodium sulfate (Na₂SO₄). Solvent was removedunder vacuum. Crude product was purified by column chromatography(normal phase silica, using gradient of 0 to 25% EtOAc in Hexane) togive 3.0 g of methyl 2-methoxy-5-morpholinonicotinate (dark green gum).Yield: 29.26%. m/z [M+2]+ 253.41 ¹H NMR (DMSO-d₆, 400 MHz) δ 8.53 (d,J=2.6 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.741(m, 4H), 3.072 (m, 4H) ppm.

Example 43—Preparation of Intermediate 16

The synthesis of intermediate 16 followed General Procedure 2 following:

In dry atmosphere with N₂ gas flow, acetonitrile (0.828 g, 0.020 mol,1.7 eq) was added to tetrahydrofuran (30 mL) and the mixture cooled to−78° C. To this was added ^(n)BuLi (2.5 M in hexane, 8.3 mL, 0.020 mol,1.7 eq) dropwise over a period of 60 minutes, and reaction was thenstirred for another 60 minutes. Methyl 2-methoxy-5-morpholinonicotinate(Intermediate 15, 3.0 g, 0.011 mol, 1.0 eq) was added in portions to thereaction mixture and the reaction mixture was stirred at −78° C. for 3hrs. The reaction was quenched with saturated ammonium chloride solutionand product was extracted with ethyl acetate. The organic phase wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography using (60-120 mesh size)silica gel, eluting with 0-40% ethyl acetate in n-hexane as mobile phaseto yield pure desired product3-(2-methoxy-5-morpholinopyridin-3-yl)-3-oxopropanenitrile (Intermediate16, 2.5 g, yield—80.64%) m/z [M+2]+ 262.20 ¹H NMR (DMSO-d₆, 400 MHz) δ8.19 (d, J=3.1 Hz, 1H), 7.72 (d, J=3.1 Hz, 1H), 4.56 (s, 2H), 3.94 (s,3H), 3.76-3.73 (m, 4H), 3.18-2.95 (m, 4H) ppm.

Example 44—Preparation of Compound 28

The synthesis of compound 28 followed General Procedure 3 following:

To a solution of3-(2-methoxy-5-morpholinopyridin-3-yl)-3-oxopropanenitrile (Intermediate16, 2.5 g, 0.0095 mol, 1.0 eq) in isopropanol (25 mL) and acetic acid(0.5 mL) was added hydrazine monohydrate (380 mg, (0.009 mol, 1.0 eq)dropwise. The reaction was stirred at 65° C. for 12 hours. Afterreaction completion (monitored by LC-MS), the mixture was concentrated.The residue was purified by column chromatography using silica gel(60-120 mesh), eluting with 0-100% ethyl acetate in n-hexane as gradientto give desired product3-(2-methoxy-5-morpholinopyridin-3-yl)-1H-pyrazol-5-amine (Compound 28,1.6 g, yield—60.83%) m/z 276.48 [M+2]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 11.70(s, 1H), 7.76 (d, J=2.8 Hz, 2H), 5.99 (s, 1H), 4.69 (s, 2H), 3.91 (d,J=11.5 Hz, 3H), 3.79-3.74 (m, 4H), 3.11-3.04 (m, 4H) ppm.

Example 45—Preparation of Compound 29

The synthesis of compound 29 followed General Procedure 13 following:

General Procedure 13

To a solution of3-(2-methoxy-5-morpholinopyridin-3-yl)-1H-pyrazol-5-amine (compound 28,1.4 g, 0.005 mol, 1.0 eq) in dry dichloromethane (140 mL) was added BBr₃(6.6 mL, 0.006 mol, 1.3 eq) dropwise at 0° C. The mixture was allowed toreach room temperature over 30 minutes, and was stirred for a further 12hours at room temperature. After reaction completion, methanol (10 mL)was added and solvents evaporated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel, elutingwith 10-15% methanol in dichloromethane as mobile phase, yieldingdesired product3-(5-amino-1H-pyrazol-3-yl)-5-morpholinopyridin-2(1H)-one (Compound 29,800 mg, yield—60.60%) m/z [M+2]+ 262.23 ¹H NMR (DMSO-d₆, 400 MHz) δ11.72 (s, 2H), 7.87 (d, J=3.0 Hz, 1H), 6.81 (s, 1H), 6.16 (s, 1H), 4.65(s, 2H), 3.75-3.67 (m, 4H), 2.93-2.85 (m, 4H) ppm.

Example 46—Preparation of Compound 30

The synthesis of Compound 30 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of3-(5-amino-1H-pyrazol-3-yl)-5-morpholinopyridin-2(1H)-one (compound 29,0.8 g, 0.0030 mol, 1.0 eq) in methanol (20 mL) was added acetic acid(0.5 mL) dropwise. To this was added 5-chlorothiophene-2-carbaldehyde(0.537 g, 0.0036 mol, 1.2 eq) portionwise. The reaction was stirred for30-45 minutes at room temperature. Sodium cyanoborohydride (0.460 g,0.0073 mol, 2.0 eq) was added portionwise over a period of 15 minutes.The reaction mixture was stirred for 12 hours. After reactioncompletion, the mixture was poured into ice cold water under stirringand extracted with ethyl acetate. The organic phase was dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography using silica gel, eluting with 2%-7%methanol in dichloromethane to yield product3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-5-morpholinopyridin-2(1H)-one(Compound 30, 1.1 g, yield—91.7%) m/z [M+2]+ 392.56 ¹H NMR (DMSO-d₆, 400MHz) δ 12.17-11.71 (m, 2H), 7.93 (d, J=2.9 Hz, 1H), 6.94 (d, J=3.7 Hz,1H), 6.88 (d, J=3.8 Hz, 1H), 6.85 (s, 1H), 6.31 (s, 1H), 4.38 (s, 2H),3.82-3.65 (m, 4H), 2.98-2.82 (m, 4H) ppm.

Example 47—Preparation of Compound 31

The synthesis of compound 31 followed General Procedure 6 following:

To a cold solution (0° C.) of pivalic acid (0.031 g, 0.0003 mol, 1.2 eq)in THF (3 mL) under nitrogen was added EDCI.HCl (0.031 g, 0.0003 mol,1.2 eq) and DIPEA (0.077 g, 0.0008 mol, 3.0 eq). The reaction mixturewas stirred for 30 minutes, followed by the addition of HOBt (0.006 g,0.00005 mol, 0.2 eq) and 3-(5-(((5-chlorothiophen-2-yl) methyl)amino)-1H-pyrazol-3-yl)-5-morpholinopyridin-2(1H)-one (Compound 30, 0.1g, 0.00026 mol, 1.0 eq). The reaction mixture was stirred for 12 hoursat room temperature. After reaction completion (monitored by LC-MS), themixture was poured into water (10 mL) and extracted with ethyl acetate(3×25 mL). The combined organic layers were washed with water, brine,dried over sodium sulfate and evaporated under reduced pressure. Theresidue was purified by preparative HPLC using water-ACN as mobile phaseto give the desired product3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-5-morpholinopyridin-2(1H)-one(Compound 31, 0.040 g, yield—32.93%) m/z 476.5 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 11.66 (s, 1H), 7.94 (d, J=3.2 Hz, 1H), 7.76 (t, J=6.3 Hz, 1H),6.97-6.93 (m, 3H), 6.22 (s, 1H), 4.48 (d, J=6.1 Hz, 2H), 3.79-3.66 (m,4H), 2.98-2.74 (m, 4H), 1.47 (s, 9H) ppm.

Example 48—Preparation of Compound 32

The synthesis of Compound 32 followed General Procedure 14 following:

General Procedure 14

To a solution of5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 23, 0.5 g, 1.29 mmol, 1.0 eq) and phenylboronic acid (0.19 g,1.55 mmol, 1.0 eq) in dioxane:water (5:1, 10 mL) was added potassiumcarbonate (0.358 g, 2.59 mmol, 2.0 eq). The reaction was then degassedunder nitrogen for 30 minutes. To this was then added1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.094 g,0.129 mmol, 0.1 eq), and the mixture was stirred at 100° C. for 5-6hours. After reaction completion, the mixture was diluted with water andextract with dichloromethane (25 mL×3). The organic phases were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel (100-200mesh), eluting with 4-5% methanol in dichloromethane as gradient to givepure desired product (Compound 32, 300 mg, yield—62%) m/z 383.31 [M+H]+¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 12.00 (s, 1H), 8.27 (d, J=2.5Hz, 1H), 7.74 (s, 1H), 7.66 (d, J=7.4 Hz, 2H), 7.43 (dd, J=16.8, 8.9 Hz,2H), 7.32 (t, J=7.3 Hz, 1H), 6.92 (dd, J=9.8, 7.2 Hz, 1H), 6.91-6.81 (m,1H), 6.32 (d, J=6.3 Hz, 1H), 5.90 (s, 1H), 4.36 (t, J=7.3 Hz, 2H) ppm.

Example 49—Preparation of Compound 33

The synthesis of Compound 33 followed General Procedure 5 following:

To a cold solution (0° C.) of3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-5-phenylpyridin-2(1H)-one(Compound 32, 0.2 g, 0.52 mmol, 1 eq) in dichloromethane (5 mL) wasadded triethylamine (TEA, 0.157 g, 1.56 mmol, 3 eq), followed bypivaloyl chloride (0.062 g, 0.52 mmol, 1 eq). The reaction mixture wasstirred at room temperature for 12 hours. After completion, the reactionmixture was diluted with water and extracted with ethyl acetate (25mL×3). The organic phase were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by Combi-flashchromatography, eluting with 0 to 60% ethyl acetate in hexane, to yielddesired product (Compound 33, 40 mg, yield—19.20%) m/z 467.52 [M+H]+ ¹HNMR (DMSO-d₆, 400 MHz) δ 12.21 (s, 1H), 8.35 (d, J=2.8 Hz, 1H), 7.78(dd, J=11.7, 5.4 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.46 (t, J=7.7 Hz,2H), 7.33 (t, J=7.3 Hz, 1H), 6.97 (dd, J=11.3, 3.7 Hz, 2H), 6.25 (s,1H), 4.50 (d, J=6.2 Hz, 2H), 1.48 (s, 9H) ppm.

Example 50—Preparation of Compound 34

The synthesis of Compound 34 followed General Procedure 15 following:

General Procedure 15

To a solution of3-(5-bromo-2-methoxypyridin-3-yl)-N-((5-chlorothiophen-2-yl)methyl)-1H-pyrazol-5-amine(Compound 25, 1.0 g, 0.0025 mol, 1.0 eq) in DMF (500 mL) was added zinccyanide (0.308 g, 0.0026 mol, 1.05 eq). The reaction mixture wasdegassed for 10 minutes, followed by the addition oftetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄, 0.436 g (0.00037mol, 0.15 eq). The reaction mixture was again degassed for 10 minutes,and then heated under microwave irradiation for 1 hour. Aftercompletion, (monitored by LC-MS), the reaction mixture was poured intowater (10 mL) and extracted with ethyl acetate (2×30 mL). The combinedorganic phases were washed with water, followed by brine, which was thendried over sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography using 60-120 mesh sizesilica gel, eluting with 0-40% ethyl acetate in n-hexane, to givedesired product5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-6-methoxynicotinonitrile(Compound 34, 0.410 g, yield—47.1%) m/z 346.4 [M+1]+ ¹H NMR (400 MHz,DMSO-d₆) δ 12.08 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 6.93 (s, 1H), 6.89(s, 1H), 6.18 (s, 1H), 6.01 (s, 1H), 4.38 (d, J=6.2 Hz, 2H), 4.05 (s,3H) ppm.

Example 51—Preparation of Compound 35

The synthesis of Compound 35 followed General Procedure 16 following:

General Procedure 16

To a sealed tube was added5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-6-methoxynicotinonitrile(Compound 34, 0.3 g, 0.0009 mol, 1.0 eq) and then pyridine hydrochloride(1.0 g, 0.0026 mol, 3.0 eq). The tube was sealed and heated to 100° C.for 6 hrs. After completion (monitored by LC-MS), the reaction mixturewas poured into saturated NaHCO₃ (8 mL) and extracted with ethylacetate. The combined organic phases were washed with water, followed bybrine, dried over sodium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography using (60-120 meshsize) silica gel, eluting with 0-5% MeOH in dichloromethane to givedesired product5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(Compound 35, 0.14 g, yield—55.58%) m/z 332.4 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 12.93 (s, 2H), 8.37 (s, 1H), 8.26 (s, 1H), 6.96 (d, J=3.8 Hz,1H), 6.92 (d, J=3.8 Hz, 1H), 6.37 (s, 1H), 4.43 (s, 2H) ppm.

Example 52—Preparation of Compound 36

The synthesis of Compound 36 followed General Procedure 6 following:

To a cold solution (0° C.) of o-anisic acid (0.077 g, 0.0005 mol, 1.2eq) in THF (10 mL) was added EDCI.HCl (0.097 g, 0.0005 mol, 1.2 eq),followed by triethylamine (TEA, 0.129 g, 0.0013 mol, 3.0 eq) undernitrogen. The reaction mixture was stirred for 30 minutes, and to it wasadded HOBt (0.011 g, 0.00008 mol, 0.2 eq), followed by5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(Compound 35). The reaction mixture was stirred at room temperature for14 hours. After completion (monitored by LC-MS), reaction mixture waspoured into water (5 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic phases were washed with water, followed by brine, andthen dried over sodium sulfate. Evaporation under reduced pressure gavea residue, which was purified by preparative HPLC using Water-ACN asmobile phase to give the desired product5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile(Compound 36, 0.035 g, yield—17.8%) m/z 466.66 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 12.74 (s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.80 (t, J=6.2 Hz, 1H),7.70 (s, 1H), 7.59-7.49 (m, 1H), 7.44 (dd, J=7.5, 1.6 Hz, 1H), 7.19 (d,J=8.4 Hz, 1H), 7.05 (dd, J=15.8, 8.5 Hz, 1H), 7.00 (d, J=3.8 Hz, 2H),6.20 (s, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.76 (s, 3H) ppm.

Example 53—Preparation of Intermediate 17

The synthesis of Intermediate 17 followed General Procedure 14following:

To a solution of methyl 5-bromo-2-methoxynicotinate (Intermediate 8, 5.0g, 0.02 mol, 1.0 eq) in dioxane:water (3:1; 80 mL) was addedmethylboronic acid (1.82 g, 0.03 mol, 1.5 eq), followed by potassiumcarbonate (8.42 g, 0.06 mol, 3 eq). The reaction mixture was degassedfor 10 minutes, followed by the addition of1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride(PdCl₂(dppf); 1.48 g, 0.002 mol, 0.1 eq). The reaction mixture was againdegassed for 10 minutes, and then stirred at 100° C. for 3 hours. Aftercompletion, monitored by LC-MS, the reaction mixture was cooled anddiluted with water (100 mL). The mixture was extracted with ethylacetate (2×60 mL), and the combined organic phases were washed withbrine, dried over sodium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography using silica gel(60-120 mesh size), eluting with 5-20% ethyl acetate in n-hexane asmobile phase to give pure desired product methyl2-methoxy-5-methylnicotinate (1.92 g; Intermediate 17; yield—52.1%) m/z182.19 [M+1]+ 1H NMR (400 MHz, DMSO) δ 8.20 (dd, J=2.4, 0.7 Hz, 1H),7.96 (dd, J=2.4, 0.7 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 2.24 (s, 3H)ppm.

Example 54—Preparation of Intermediate 18

The synthesis of Intermediate 18 followed General Procedure 2 following:

To a dry (N₂ gas flow) and cooled solution (−78° C.) of acetonitrile(0.883 g, 0.022 mol, 1.5 eq) in tetrahydrofuran (30 mL) was added^(n)BuLi (2.5M in hexane, 8.6 mL, 0.022 mol, 1.5 eq) dropwise over aperiod of 20 minutes. The reaction was stirred for a further 60 minutes.Methyl 2-methoxy-5-methylnicotinate (Intermediate 17, 2.6 g, 0.014 mol,1.0 eq) was added portionwise and the reaction mixture maintained at−78° C. for 3 hrs. The reaction mixture was quenched with saturatedammonium chloride solution, and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing silica gel (60-120 mesh size), eluting with 10-40% ethyl acetatein n-hexane as mobile phase, to give pure desired product3-(2-methoxy-5-methylpyridin-3-yl)-3-oxopropanenitrile (Intermediate 18,2.05 g, yield—75.1%) m/z 191.19 [M+1]+ ¹H NMR (400 MHz, CDCl3) δ 8.23(t, J=4.4 Hz, 1H), 8.05 (dd, J=2.5, 0.5 Hz, 1H), 4.16 (s, 2H), 4.09 (s,3H), 2.32 (s, 3H) ppm.

Example 55—Preparation of Compound 37

The synthesis of compound 37 followed General Procedure 3 following:

To a solution of3-(2-methoxy-5-morpholinopyridin-3-yl)-3-oxopropanenitrile (Intermediate18, 2.0 g, 0.011 mol, 1.0 eq) in isopropanol (10 mL) and acetic acid(0.2 mL) was added hydrazine monohydrate (0.789 g, 0.016 mol, 1.5 eq)dropwise. The reaction was stirred at 60° C. for 3 hours. The reactionmixture was monitored by LC-MS, and after completion was concentratedunder reduced pressure. The residue was purified by columnchromatography using silica gel (60-120 mesh), eluting with 0-5%methanol in dichloromethane, to give desired product3-(2-methoxy-5-methylpyridin-3-yl)-1H-pyrazol-5-amine (Compound 37, 2.01g, yield—93.6%) m/z 205.54 [M+1]+ ¹H NMR (400 MHz, DMSO) δ 11.28 (s,1H), 7.92-7.90 (m, 2H), 5.93 (s, 1H), 4.72 (s, 2H), 3.91 (s, 3H), 2.24(s, 3H) ppm.

Example 56—Preparation of Compound 38

The synthesis of compound 38 followed General Procedure 16 following:

A mixture of 3-(2-methoxy-5-methylpyridin-3-yl)-1H-pyrazol-5-amine(Compound 37, 0.5 g, 0.0024 mol, 1.0 eq) and pyridine hydrochloride(1.697 g, 0.0147 mol, 6.0 eq) in a sealed tube was heated at 100° C. for14 hours. The reaction was monitored by LC-MS. After completion, themixture was mixed with saturated sodium bicarbonate (50 mL) andextracted with ethyl acetate (2×20 mL). The combined organic phases werewashed with water, then brine, dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by columnchromatography using silica gel (60-120 mesh size), eluting with 0-6%methanol in dichloromethane as mobile phase to give pure desired product3-(5-amino-1H-pyrazol-3-yl)-5-methylpyridin-2(1H)-one (Compound 38,0.330 g, yield—70.9%) m/z 191.05 [M+1]+ ¹H NMR (400 MHz, DMSO) δ 11.83(s, 2H), 7.78 (d, J=2.3 Hz, 1H), 7.20 (s, 1H), 6.03 (s, 1H), 4.72 (m,2H), 2.08 (s, 3H) ppm.

Example 57—Preparation of Compound 39

The synthesis of Compound 39 followed General Procedure 4 following:

To a cooled solution (0-10° C.) of methanol (10 mL) and acetic acid(0.103 g, 0.002 mol, 1.0 eq) was added3-(5-amino-1H-pyrazol-3-yl)-5-methylpyridin-2(1H)-one (Compound 38,0.330 g, 0.0017 mol, 1.0 eq) portionwise. To this was then added5-chlorothiophene-2-carbaldehyde (0.278 g, 0.0019 mol, 1.1 eq), alsoportionwise. Cooling was removed and the reaction then stirred for afurther 30-45 minutes at room temperature. To the mixture was then addedsodium cyanoborohydride (0.325 g, 0.0052 mol, 3.0 eq) portionwise over aperiod of 15 minutes. The reaction was stirred for a further 3 hours.After reaction completion, the reaction mixture was poured into ice coldwater under stirring and extracted with ethyl acetate (2×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel, eluting with 0-1% methanol indichloromethane as mobile phase, to give desired product3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-5-methylpyridin-2(1H)-one(Compound 39, 0.310 g, yield—55.7%) m/z 321.49 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 11.83 (s, 2H), 7.78 (d, J=2.4 Hz, 1H), 7.21 (s, 1H), 6.92 (t,J=7.3 Hz, 1H), 6.87 (d, J=3.7 Hz, 1H), 6.09 (d, J=14.3 Hz, 1H), 5.88 (t,J=6.0 Hz, 1H), 4.35 (d, J=6.3 Hz, 2H), 2.08 (s, 3H) ppm.

Example 58—Preparation of Compound 40

The synthesis of Compound 40 followed General Procedure 6 following:

To a cooled (0° C.) and dry (nitrogen) solution of furan-3-carboxylicacid (0.104 g, 0.935 mmol, 1.2 eq) in THF (5 mL) was added EDCI.HCl(0.179 g, 0.935 mmol, 1.2 eq), followed by trimethylamine (0.238 g, 2.33mmol, 3.0 eq). The reaction mixture was stirred for 30 minutes, and toit was added HOBt (0.021 g, 0.155 mmol, 0.2 eq.), followed by3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-5-methylpyridin-2(1H)-one(Compound 39). The reaction was monitored by LC-MS, and after reactioncompletion the mixture was poured into water (5 mL) and extracted withethyl acetate (3×25 mL). The organic phases were washed with water, thenbrine, and dried over sodium sulfate and evaporated under reducedpressure. The residue was purified by preparative HPLC, eluting withammonia-water to give the desired product Compound 40 (0.055 g,yield—17.0%) m/z 415.51 [M+1]+ ¹H NMR (400 MHz, DMSO) δ 11.72 (s, 1H),9.06 (d, J=0.8 Hz, 1H), 8.11 (d, J=2.6 Hz, 1H), 7.89 (t, J=1.7 Hz, 1H),7.82 (t, J=6.2 Hz, 1H), 7.29 (s, 1H), 7.08 (dd, J=7.3, 5.9 Hz, 1H),7.01-6.93 (m, 2H), 6.33 (d, J=6.5 Hz, 1H), 4.54 (d, J=6.1 Hz, 2H), 2.12(s, 3H) ppm.

Example 59—Preparation of Intermediate 19

The synthesis of Intermediate 19 followed General Procedure 12following:

To a solution of commercially available methyl2-bromo-6-methoxyisonicotinate (0.45 g, 1.83 mmol, 1.0 eq) in1,4-dioxane (5 mL) was added morpholine (0.319 g, 3.67 mmol, 2.0 eq),followed by cesium carbonate (1.19 g, 3.67 mmol, 2.0 eq. The reactionmixture was degassed, bubbling with argon for 30 minutes. To the mixturewas added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos,0.052 g, 0.091 mmol, 0.05 eq) all at once, followed bytris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃, 0.083 g, 0.091mmol, 0.05 eq). The reaction mixture was stirred at 90° C. for 5 hours.After completion of reaction, the mixture was cooled to roomtemperature, filtered through a bed of Celite and washed with ethylacetate (50 mL×3). The organic phases were combined and concentratedunder reduced pressure. The residue was purified by Combi-flash columnchromatography (230-400 silica gel), eluting with 3-4% ethyl acetate inhexane to give methyl 2-methoxy-6-morpholinoisonicotinate (Intermediate19, 0.341 g) as a pale yellow solid. Yield: 73.59% [m/z=253.4 (m+1)] ¹HNMR (CDCl₃, 400 MHz) δ 6.79 (s, 1H), 6.69 (d, J=0.8 Hz, 1H), 3.92 (d,J=2.6 Hz, 6H), 3.88-3.83 (m, 4H), 3.60-3.52 (m, 4H) ppm.

Example 60—Preparation of Intermediate 20

The synthesis of Intermediate 20 followed General Procedure 2 following:

To a cooled solution (−78° C.) of acetonitrile (0.072 g, 1.78 mmol, 1.5eq) in dry tetrahydrofuran (4 mL) was added ^(n)BuLi (2.5M in hexane,0.71 mL, 1.78 mmol, 1.5 eq) dropwise over a period of 30 minutes. Thereaction was stirred for another 30 minutes, and then methyl2-methoxy-6-morpholinoisonicotinate (Intermediate 19, 0.34 g, 1.19 mmol,1.0 eq) was added portionwise. The reaction mixture was stirred at −78°C. for a further 3 hours. After completion, the mixture was quenchedwith saturated ammonium chloride solution. The product was thenextracted with ethyl acetate, and the organic layer was dried oversodium sulfate and evaporated under reduced pressure. The resultantyellow sticky solid was triturated in diethyl ether to obtain therequired product3-(2-methoxy-6-morpholinopyridin-4-yl)-3-oxopropanenitrile (0.31 g, darkyellow solid). The crude product was carried to the next step withoutfurther purification (Yield: 96.5%), m/z=262.20 (m+1)⁺.

Example 61—Preparation of Compound 41

The synthesis of Compound 41 followed General Procedure 3 following:

To a solution of3-(2-methoxy-6-morpholinopyridin-4-yl)-3-oxopropanenitrile (Intermediate20, 0.32 g, 1.22 mmol, 1.0 eq) in isopropanol (4 mL) and acetic acid(0.073 mL) was added hydrazine monohydrate (0.073 g, 1.46 mmol, 1.2 eq)dropwise. The reaction was then stirred at 65° C. for 12 hours. Aftercompletion (monitored by LC-MS), the reaction mixture was concentratedunder reduced pressure. The residue was purified by columnchromatography using silica gel (60-120 mesh), eluting with 50-60% ethylacetate in n-hexane as gradient to give desired product3-(2-methoxy-6-morpholinopyridin-4-yl)-1H-pyrazol-5-amine (Compound 41,0.21 g, yield—62.3%) m/z=276.48 [M+1]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 6.60(s, 1H), 6.36 (s, 1H), 5.85 (s, 1H), 4.85 (s, 2H), 3.79 (s, 3H),3.76-3.64 (m, 4H), 3.54-3.42 (m, 4H) ppm.

Example 62—Preparation of Compound 42

The synthesis of Compound 42 followed General Procedure 17 following:

General Procedure 17

3-(2-methoxy-6-morpholinopyridin-4-yl)-1H-pyrazol-5-amine (Compound 41,0.15 g, 0.544 mmol, 1.0 eq) was dissolved in cone. HCl (1 mL) and heatedto reflux at 100° C. for 5 h. After completion, reaction mass wasconcentrated under vacuum. The residue was dissolved in methanol andbasified with solid bicarbonate to basic pH. Methanol was filtered andconcentrated under vacuum to obtain a dark brown solid as desiredproduct 4-(5-amino-1H-pyrazol-3-yl)-6-morpholinopyridin-2(1H)-one(Compound 42, 0.120 g, yield: 84.5%); m/z=262.23 (m+1)+ ¹H NMR (400 MHz,DMSO) δ 6.37 (s, 1H), 6.17 (s, 1H), 5.78 (s, 1H), 4.85 (s, 2H),3.74-3.63 (m, 4H), 3.30-3.40 (m, 4H) ppm.

Example 63—Preparation of Compound 43

The synthesis of Compound 43 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of4-(5-amino-1H-pyrazol-3-yl)-6-morpholinopyridin-2(1H)-one (Compound 42,0.12 g, 0.46 mmol, 1.0 eq) in methanol (2 mL) was added acetic acid(0.03 mL, 0.69 mmol, 1.1 eq), followed by5-chlorothiophene-2-carbaldehyde (0.1 g, 0.69 mmol, 1.5 eq) portionwise.The reaction was then stirred for 45 minutes at room temperature. Sodiumcyanoborohydride (0.042 g, 0.69 mmol, 1.5 eq) was added portionwise overa period of 15 minutes. The reaction was then stirred for a further 12hours. After completion, the reaction mixture was poured into ice coldwater under stirring and extracted with 10% methanol in dichloromethane.The organic phase was dried over sodium sulfate and concentrated underreduced pressure. The residue was triturated with ethyl acetate, and theresultant solid was desired product4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-6-morpholinopyridin-2(1H)-one(Compound 43, 0.051 g, brown solid, yield—27.8%); m/z=392.56 (m+1) ¹HNMR (DMSO-d₆, 400 MHz) δ 7.00-6.83 (m, 2H), 6.38 (s, 1H), 6.17 (s, 1H),5.98 (s, 1H), 4.36 (d, J=6.1 Hz, 2H), 3.69 (s, 4H), 3.38 (s, 4H) ppm.

Example 64—Preparation of Compound 44

The synthesis of Compound 44 followed General Procedure 6 following:

To a cooled solution (0° C.) of pivalic acid (0.022 g, 0.22 mmol, 1.4eq) in THF (1 mL) was added EDCI.HCl (0.044 g, 0.15 mmol, 1.5 eq), HOBt(0.01 g, 0.08 mmol, 0.5 eq) and DIPEA (0.07 mL, 0.39 mmol, 2.5 eq) undernitrogen. The reaction mixture was stirred for 30 minutes and to thismixture was added 4-(5-(((5-chlorothiophen-2-yl) methyl)amino)-1H-pyrazol-3-yl)-6-morpholinopyridin-2(1H)-one (Compound 43, 0.05g, 0.16 mmol, 1.0 eq). The reaction mixture was stirred for 12 hours atroom temperature. After completion (monitored by LC-MS), the reactionmixture was poured into water (10 mL) and extracted with ethyl acetate(3×25 mL). The combined organic phases were washed with water, brine,dried over sodium sulfate and evaporated under reduced pressure. Theresidue was purified by preparative HPLC using water-acetonitrile as themobile phase, to yield the desired product4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-6-morpholinopyridin-2(1H)-one(Compound 44, 0.008 g) m/z=476.5 [M+1]+ ¹H NMR (400 MHz, DMSO-d₆) δ12.33 (s, 1H), 7.08-6.84 (m, 3H), 6.64 (s, 1H), 6.19 (s, 1H), 5.99 (s,1H), 4.37 (d, J=6.3 Hz, 2H), 3.70 (s, 4H), 3.43 (d, J=21.8 Hz, 4H), 1.29(s, 9H) ppm.

Example 65—Preparation of Intermediate 21

The synthesis of Intermediate 21 followed General Procedure 14following:

To a solution of methyl 5-bromo-6-methoxynicotinate (Intermediate 13,8.0 g, 0.034 mol, 1.0 eq) in dioxane:water (4:1, 64:16 mL) was addedpotassium carbonate (8.2 g, 0.083 mol, 2.5 eq), followed bymethylboronic acid (3.0 g, 0.049 mol, 1.5 eq). The mixture was degassedfor 20 minutes by bubbling through a stream of argon, followed by theaddition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂, 2.39 g, 3.3 mmol, 0.1 eq). The reaction mixture wasstirred at 100° C. for 4 hours. The reaction progress was monitored byLCMS. After reaction completion, the mixture was diluted with cold waterand extracted with ethyl acetate (3×100 mL). The combined organic phaseswere dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography using silica(100-200 mesh size), eluting with 3% ethyl acetate in hexane. Purefractions were concentrated under reduced pressure and dried undervacuum to give desired product (Intermediate 21, 1.5 g, yield—91%) m/z182.1 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 8.58 (d, J=2.0 Hz, 1H),8.05-7.97 (m, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 2.18 (s, 3H) ppm.

Example 66—Preparation of Intermediate 22

The synthesis of Intermediate 22 followed General Procedure 2 following:

Under an inert and dry N₂ atmosphere, acetonitrile (0.564 g, 0.014 mol,1.7 eq) was added to tetrahydrofuran (20 mL) and the solution thencooled to −78° C. To this was added ^(n)BuLi (2.5M in hexane, 5.6 mL,0.014 mol, 1.7 eq) dropwise over a period of 60 minutes, and thereaction was stirred for another 60 minutes. Methyl6-methoxy-5-methylnicotinate (Intermediate 13, 1.5 g, 8.3 mmol, 1.0 eq.)was added portionwise to the reaction mixture, and the temperaturemaintained at −78° C. for a further 3 hours. The reaction progress wasmonitored by LCMS. After completion, the reaction was quenched withethyl acetate and the total reaction mixture was concentrated underreduced pressure. The crude residue was triturated with diethyl etherand dried under reduced pressure to obtain product desired product3-(2-methoxy-5-methyl-1,6-dihydropyridin-3-yl)-3-oxopropanenitrile(Intermediate 21), which was used directly in the next step. 1.5 g(yield—95.5%) m/z [M+1]+ 191.15.

Example 67—Preparation of Compound 45

The synthesis of Compound 45 followed General Procedure 3 following:

To a solution of3-(2-methoxy-5-methyl-1,6-dihydropyridin-3-yl)-3-oxopropanenitrile(Intermediate 21, 1.5 g, 7.9 mmol, 1.0 eq) in isopropanol (20 mL) wasadded acetic acid (0.5 mL). To this was added hydrazine monohydrate(0.592 g, 12 mmoles, 1.5 eq) dropwise, and the reaction was then stirredat 80° C. for 4 hours. The reaction progress was monitored by LCMS.After completion, the reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography using silicagel (100-200 mesh), eluting with 5% methanol in dichloromethane asgradient, to give desired product3-(6-methoxy-5-methylpyridin-3-yl)-1H-pyrazol-5-amine (Compound 45, 1.0g, yield—62.11%) m/z [M+1]+ 205.20.

Example 68—Preparation of Compound 46

The synthesis of Compound 46 followed General Procedure 17 following:

A mixture of 3-(6-methoxy-5-methylpyridin-3-yl)-1H-pyrazol-5-amine(Compound 45, 1.0 g, 4.9 mmol, 1.0 eq) in concentrated HCl (20 mL) wasallowed to stir at 100° C. for 12 hours. The reaction progress wasmonitored by LCMS. After completion of reaction, the reaction mixturewas concentrated under vacuum and diluted with methanol. The basicitywas adjusted to above pH 7 using solid potassium carbonate, thenfiltered. The filtrate was concentrated on reduced pressure, and thenpurified by washing with ethyl acetate (3×10 mL) and dried on vacuum togive desired product5-(5-amino-1H-pyrazol-3-yl)-3-methylpyridin-2(1H)-one (Compound 46, 0.8g, yield—85.92%) m/z [M+1]+ 191.2.

Example 69—Preparation of Compound 47

The synthesis of Compound 47 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of5-(5-amino-1H-pyrazol-3-yl)-3-methylpyridin-2(1H)-one (Compound 46, 0.7g, 3.6 mmol, 1.0 eq) in methanol (20 mL) was added acetic acid (0.5 mL)dropwise. To this was then added 5-chlorothiophene-2-carbaldehyde (0.805g, 5.8 mmol, 1.5 eq) portionwise, and the reaction mixture was stirredfor 30-45 minutes at room temperature. Sodium cyanoborohydride (0.462 g,7.4 mmol, 2.0 eq) was added portionwise over a period of 15 minutes. Thereaction was stirred for 12 hours. After completion of reaction,methanol was evaporated off and the residue was dissolved in ice coldwater and extracted with ethyl acetate (3×30 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing silica gel (100-200 mesh), eluting with 7% methanol indichloromethane as mobile phase to give pure desired product5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpyridin-2(1H)-one(Compound 47, 0.2 g, yield—16.97%) m/z [M+1]+ 321.25 ¹H NMR (DMSO-d₆,400 MHz) δ 11.73 (s, 2H), 7.59 (d, J=35.9 Hz, 2H), 7.04-6.82 (m, 2H),5.92 (s, 1H), 5.74 (s, 1H), 4.33 (d, J=6.3 Hz, 2H), 2.01 (s, 3H) ppm.

Example 70—Preparation of Compound 48

The synthesis of Compound 48 followed General Procedure 6 following:

To a cooled solution (0° C.) of pivalic acid (0.15 g, 0.52 mmol, 1.1 eq)in THF was added EDC.HCl (0.134 g, 0.7 mmol, 1.5 eq), HOBT (0.031 g,0.23 mmol, 0.5 eq) and DIEA (0.152 g, 1.17 mmol, 2.5 eq). The reactionmixture was allowed to stir at 0° C. for 20 minutes, followed by theportionwise addition of5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpyridin-2(1H)-one(Compound 47, 0.15 g, 0.47 mmol, 1.0 eq). The reaction mixture wasallowed to stir at room temperature for 12 hours. After completion ofreaction, the reaction mixture was diluted with water and extracted withethyl acetate (3×50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC usingacetonitrile/water as the mobile phase to obtain desired product afterlyophilization:5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-3-methylpyridin-2(1H)-one (Compound 48, 0.044 g, yield—17.46%) m/z [M+1]+405.23. ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 7.83 (t, J=6.3 Hz,1H), 7.79-7.66 (m, 2H), 7.04 (d, J=3.8 Hz, 1H), 6.97 (d, J=3.7 Hz, 1H),5.94 (s, 1H), 4.45 (d, J=6.3 Hz, 2H), 2.04 (s, 3H), 1.45 (s, 9H) ppm.

Example 71—Preparation of Intermediate 22

The synthesis of Intermediate 22 followed General Procedure 2 following:

In dry N₂ condition, acetonitrile (3 g, 73 mmol, 1.7 eq) was added totetrahydrofuran (150 mL), and the solution cooled to −78° C. To this wasthen added ^(n)BuLi (2.5M in hexane, 30 mL, 48 mmol, 1.7 eq) dropwiseover a period of 60 minutes, and the reaction was then stirred foranother 60 minutes. Methyl5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (Intermediate 11, 10 g,43 mmol, 1.0 eq) was added in portions to the reaction mixture at −78°C. and the mixture stirred for 3 hours, and then warmed to roomtemperature for 3-4 hours. Ethyl acetate (5 mL) was added slowly. Thereaction mixture was evaporated off, then the residue washed with hexane(100 mL×2) and ethyl acetate (100 mL×2). The solid compound was driedunder reduced pressure to give desired product (10 g, yield—37.80%)which was directly used in next step without purification. m/z 239.12[M−H]−.

Example 72—Preparation of Intermediate 23

The synthesis of Intermediate 23 followed General Procedure 3 following:

To solution of3-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropanenitrile(Intermediate 22, 10.0 g, 41 mmol, 1.0 eq) in isopropanol (150 mL) andacetic acid (2.49 g, 41 mmol, 1.0 eq) was added hydrazine monohydrate(3.11 mL, 62 mmol, 1.5 eq) dropwise. The reaction was stirred at 85° C.for 5 hours. The reaction mixture was monitored by LC-MS. Aftercompletion, the reaction mixture was concentrated to give a residue,which was purified by column chromatography by using silica gel (60-120mesh). The product was eluted using 8-9% methanol in dichloromethane asgradient to give desired product (7 g, yield—66.2%) m/z 256.85 [M+H]+ ¹HNMR (DMSO-d₆, 400 MHz) δ 9.93 (s, 2H), 8.23 (d, J=2.3 Hz, 1H), 7.73 (d,J=2.3 Hz, 1H), 5.63 (s, 1H), 4.92 (s, 2H) ppm.

Example 73—Preparation of Compound 49

The synthesis of Compound 49 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of5-(5-amino-1H-pyrazol-3-yl)-3-bromopyridin-2(1H)-one (Intermediate 23, 6g, 23 mmol, 1 eq) in methanol (60 mL) was added acetic acid (1.41 g, 23mmol, 1 eq) dropwise. To this was then added5-chlorothiophene-2-carbaldehyde (3.41 g, 23 mol, 1 eq) dropwise, andthe reaction was stirred for a further 2-3 hours at room temperature.The mixture was cooled to 0° C., and to it was added sodiumcyanoborohydride (2.96 g, 47 mmol, 2 eq) portionwise over a period of 45minutes and stirred for a further 2 hours. The reaction was monitored byLC-MS. After completion of reaction, the mixture was concentrated andresidue was poured into ice cold water under stirring. The product wasextracted with 10% methanol in dichloromethane. The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography using neutral silica gel,eluting with 8-9% methanol in dichloromethane to give pure desiredproduct (5.5 g, yield—60.90%) m/z [M+H]− 385.34 ¹H NMR (DMSO-d₆, 400MHz) δ 12.07 (s, 2H), 8.25 (d, J=2.3 Hz, 1H), 7.76 (s, 1H), 6.92 (t,J=5.9 Hz, 1H), 6.88 (d, J=3.7 Hz, 1H), 6.00 (s, 1H), 5.83 (s, 1H), 4.33(d, J=6.3 Hz, 2H) ppm.

Example 74—Preparation of Compound 50

The synthesis of Compound 50 followed General Procedure 14 following:

To a solution of3-bromo-5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 49, 0.5 g, 1.29 mmol, 1.0 eq) and phenylboronic acid (0.19 g,1.55 mmol, 1.0 eq) in dioxane:water (5:1, 10 mL) was added potassiumcarbonate (0.358 g, 2.59 mmol, 2.0 eq). The mixture was degassed by acontinuous flow of nitrogen for 30 minutes, and to it was added 1,1′-bis(diphenylphosphino) ferrocene palladium(II) dichloride (0.094 g, 0.13mmol, 0.1 eq). The reaction mixture was stirred at 100° C. for 6 hours.After completion (monitored by LC-MS), the reaction mixture was cooledto room temperature, diluted with water and extracted withdichloromethane (25 mL×3). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography using neutral silica gel (100-200mesh), eluting with 3-4% methanol in dichloromethane to give puredesired product (250 mg, yield—51%) m/z 383.31 [M+H]+ ¹H NMR (DMSO-d₆,400 MHz) δ ¹H NMR (400 MHz, DMSO) δ 12.09-12.00 (m, 1H), 11.94-11.83 (m,1H), 7.95 (s, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.49-7.31 (m, 4H), 6.93 (d,J=3.7 Hz, 1H), 6.89 (s, 1H), 5.87 (s, 1H), 4.34 (d, J=6.5 Hz, 2H) ppm.

Example 75—Preparation of Compound 51

The synthesis of Compound 51 followed General Procedure 5 following:

To a cooled solution (0° C.) of5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-phenylpyridin-2(1H)-one(Compound 50, 0.2 g, 0.52 mmol, 1 eq) in dichloromethane (5 ml) wasadded triethylamine (0.157 g, 1.56 mmol, 3 eq), followed by pivaloylchloride (0.062 g, 0.52 mmol, 1 eq). The reaction mixture was stirred atroom temperature for 12 hours. After completion, the reaction mixturewas diluted with water and extracted with ethyl acetate (25 mL×3). Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by preparative HPLC to givepure desired product (60 mg, yield—28.30%) m/z 467.31 [M+H]+ ¹H NMR(DMSO-d₆, 400 MHz) δ 12.12 (s, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.86 (dd,J=12.2, 4.5 Hz, 2H), 7.70 (d, J=7.1 Hz, 2H), 7.43 (t, J=7.5 Hz, 2H),7.36 (t, J=7.3 Hz, 1H), 7.05 (d, J=3.8 Hz, 1H), 6.97 (d, J=3.7 Hz, 1H),6.06 (s, 1H), 4.47 (d, J=6.3 Hz, 2H), 1.34 (d, J=87.2 Hz, 9H) ppm.

Example 76—Preparation of Compound 52

The synthesis of Compound 52 followed General Procedure 6 following:

To a solution of 2-methoxybenzoic acid (0.078 g, 0.51 mmol, 1 eq) inacetonitrile:THF (1:1, 5 ml) was added DIPEA (0.2 mL, 1.55 mmol, 3 eq),followed byN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 0.296 g, 0.77 mmol, 1.5 eq). Themixture was stirred at room temperature for 1 hour. To this was thenadded3-bromo-5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 49, 0.2 g, 0.51 mmol, 1.0 eq), and the mixture allowed to stirat room temperature for 12 hours. After completion, the reaction mixturewas diluted with water and extract with ethyl acetate (25 mL×3). Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by preparative HPLC to givepure desired product (75 mg, yield—27.8%) m/z 521.57 [M+H]+ ¹H NMR(DMSO-d₆, 400 MHz) δ 12.42 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.87 (t,J=6.3 Hz, 1H), 7.81 (s, 1H), 7.56-7.48 (m, 1H), 7.42 (dd, J=7.5, 1.5 Hz,1H), 7.18 (d, J=8.4 Hz, 1H), 7.14-7.03 (m, 2H), 6.99 (t, J=6.2 Hz, 1H),6.10 (s, 1H), 4.51 (d, J=6.2 Hz, 2H), 3.75 (s, 3H) ppm.

Example 77—Preparation of Compound 53

The synthesis of Compound 53 followed General Procedure 14 following:

To a solution of3-bromo-5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 49, 0.5 g, 1.29 mmol, 1.0 eq) and pyridine-3-boronic acid(0.19 g, 1.55 mmol, 1.0 eq) in dioxane:water (5:1; 10 mL) was addedpotassium carbonate (0.358 g, 2.59 mmol, 2.0 eq) was added. The reactionmixture was degassed under nitrogen for 30 minutes, and to it was added1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.094 g,0.13 mmol, 0.1 eq). The mixture was stirred at 100° C. for 5-6 hours.After completion (monitored by LC-MS), the reaction mixture was dilutedwith water and extracted with dichloromethane (25 mL×3). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing neutral silica gel (100-200 mesh), eluting with 8-9% methanol indichloromethane as gradient to give pure desired product (200 mg,yield—40%) m/z 384.7 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 11.89 (s, 2H),8.95 (s, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.07(d, J=2.5 Hz, 1H), 7.78 (s, 1H), 7.43 (dt, J=33.8, 16.9 Hz, 1H),6.99-6.90 (m, 1H), 6.89 (d, J=3.5 Hz, 1H), 5.91 (s, 2H), 4.34 (t, J=6.2Hz, 2H) ppm.

Example 78—Preparation of Compound 54

The synthesis of Compound 54 followed General Procedure 6 following:

To a solution of pivalic acid (0.053 g, 0.52 mmol, 1 eq) in DMF (5 ml)was added DIPEA (0.2 mL, 1.56 mmol, 3 eq), followed byN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 0.296 g, 0.78 mmol, 1.5 eq). Thereaction mixture was stirred at room temperature for 1 hour. To thismixture was then added5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-[3,3′-bipyridin]-2(1H)-one(Compound 54, 0.2 g, 0.52 mmol, 1.0 eq), and the mixture was allowed tostir at ambient temperature for 12 hours. After completion, the reactionmixture was diluted with water and extracted with ethyl acetate (25mL×3). The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give pure desired product (50 mg, yield—23.2%) m/z468.57 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 12.25 (s, 1H), 8.88 (d, J=1.6Hz, 1H), 8.55 (dd, J=4.8, 1.6 Hz, 1H), 8.20-8.12 (m, 1H), 8.08 (d, J=2.5Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.86 (t, J=6.5 Hz, 1H), 7.46 (dd,J=8.0, 4.8 Hz, 1H), 7.05 (d, J=3.8 Hz, 1H), 6.97 (d, J=3.7 Hz, 1H), 6.08(s, 1H), 4.47 (d, J=6.3 Hz, 2H), 1.45 (s, 9H) ppm.

Example 79—Preparation of Intermediate 24

The synthesis of Intermediate 24 followed General Procedure 2 following:

To a cooled solution (−78° C.) of acetonitrile (2.4 g, 83 mmol, 1.7 eq)in dry tetrahydrofuran (200 mL) was added ^(n)BuLi (2.5M in hexane, 33.2mL, 83 mmol, 1.7 eq) in a dropwise fashion over a period of 60 minutes.The reaction was stirred for a further 60 minutes. To this was thenadded commercially available methyl 2-bromo-6-methoxyisonicotinate (12.0g, 49 mmol, 1.0 eq) portionwise, and the reaction mixture maintained at−78° C. for 3 hrs. The reaction mixture was quenched with saturatedammonium chloride, and extracted with ethyl acetate. The organic layerswere dried over sodium sulfate and evaporated to give desired productwhich was used in next step without further purification (11.5 g,yield—92.3%) m/z 355.12 [M+H]+.

Example 80—Preparation of Compound 55

The synthesis of Compound 55 followed General Procedure 3 following:

To a solution of 3-(2-bromo-6-methoxypyridin-4-yl)-3-oxopropanenitrile(Intermediate 24, 11.5 g, 45 mmol, 1.0 eq) in isopropanol (120 mL) andacetic acid (2.7 g) was added hydrazine monohydrate (7.4 mL, 148 mmol,1.2 eq) dropwise. The reaction was stirred at 85° C. for 4-5 hours. Thereaction was monitored by LC-MS, and was then concentrated under reducedpressure. The residue was purified by column chromatography usingneutral silica gel (60-120 mesh), eluting with 3-6% methanol indichloromethane as gradient to give desired product (11 g, yield—90.3%)m/z 271.13 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 13.06-10.70 (m, 1H), 7.49(d, J=1.0 Hz, 1H), 7.07 (d, J=1.0 Hz, 1H), 5.90 (s, 1H), 5.03 (d, J=98.1Hz, 2H), 3.86 (s, 3H) ppm.

Example 81—Preparation of Compound 56

The synthesis of Compound 56 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of3-(2-bromo-6-methoxypyridin-4-yl)-1H-pyrazol-5-amine (Compound 55, 11.0g, 43 mmol, 1 eq) in methanol (220 mL) was added acetic acid (5 mL)dropwise. To this was then added 5-chlorothiophene-2-carbaldehyde (7.44g, 50.9 mmol, 1.2 eq) dropwise, and the reaction was stirred for afurther 5-6 hours at room temperature. Sodium cyanoborohydride (6.42 g,86 mmol, 2 eq) was added portionwise over a period of 45 minutes, andthe reaction was stirred for a further 12 hours. After completion ofreaction, the reaction mixture was concentrated and residue was dilutedwith water. The product was extracted with ethyl acetate. The organiclayers were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography usingneutral silica gel and product, eluting with 10-30% ethyl acetate inhexanes as mobile phase to give pure desired product (7.5 g,yield—44.1%) m/z [M+H]+ 401.31 ¹H NMR (DMSO-d₆, 400 MHz) δ 12.33 (d,J=106.6 Hz, 1H), 7.52 (s, 1H), 7.10 (s, 1H), 6.94 (s, 2H), 6.04 (s, 1H),4.36 (d, J=6.2 Hz, 2H), 3.86 (s, 3H) ppm.

Example 82—Preparation of Compound 57

The synthesis of Compound 57 followed General Procedure 17 following:

In a round-bottomed flask,3-(2-bromo-6-methoxypyridin-4-yl)-1H-pyrazol-5-amine (Compound 55, 2.0g, 7.4 mmol, 1.0 eq) was dissolved in HBr in acetic acid (30%, 20.0 mL).The mixture was stirred at 120° C. for 5-6 hours. After completion ofreaction, volatiles were distilled off to give a crude gum, which wasdissolved in dichloromethane:methanol (50:50) and neutralized by aq.K₂CO₃. The precipitates were filtered and the filtrate was evaporated todryness to give desired product (1.8 g, yield—57%) m/z 255.32 [M+H]+ ¹HNMR (400 MHz, DMSO-d₆) δ 11.75 (s, 2H), 7.32 (d, J=0.7 Hz, 1H), 6.86 (d,J=0.9 Hz, 1H), 5.81 (d, J=34.2 Hz, 1H), 5.06 (s, 2H) ppm.

Example 83—Preparation of Compound 58

The synthesis of Compound 58 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of4-(5-amino-1H-pyrazol-3-yl)-6-bromopyridin-2(1H)-one (Compound 57, 2.0g, 7.8 mmol, 1 eq) in methanol (20 mL) was added acetic acid (1 mL)dropwise. To this was then added 5-chlorothiophene-2-carbaldehyde (1.15g, 9.4 mmol, 1.2 eq) dropwise. The reaction mixture was stirred for 5-6hours at room temperature. Sodium cyanoborohydride (1.0 g, 15.6 mmol, 2eq) was added portionwise over a period of 45 minutes. and the reactionwas stirred for a further 12 hours. After completion, volatiles weredistilled off and the residue was diluted with water. The mixture wasextracted with ethyl acetate (40 mL×3). The organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography using neutral silica gel andproduct eluted with 80-90% ethyl acetate in hexanes as mobile phase togive pure desired product (1.5 g, yield—51%) m/z [M+H]+ 387.23 ¹H NMR(DMSO-d₆, 400 MHz) δ 12.25 (s, 1H), 11.61 (s, 1H), 7.35 (s, 1H),7.05-6.75 (m, 3H), 6.09 (s, 2H), 4.36 (d, J=5.9 Hz, 2H) ppm.

Example 84—Preparation of Compound 59

The synthesis of Compound 59 followed General Procedure 6 following:

To a solution of pivalic acid (0.16 g, 1.3 mmol, 1 eq) in THF:MeCN (1:1;10 mL) was added DIPEA (0.5 g, 3.89 mmol, 3 eq), followed byN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 0.74 g, 1.94 mmol, 1.5 eq). Thereaction mixture was stirred at room temperature for 1 hour. Then6-bromo-4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 58, 0.5 g, 1.29 mmol, 1.0 eq) was added, and the mixturestirred at ambient temperature for 12 hours. After completion, thereaction mixture was diluted with water and extract with dichloromethane(25 mL×3). The organic layers were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give pure desired product (10 mg, yield—2%) m/z471.52 [M+H]+ ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.90 (t, J=6.3Hz, 1H), 7.41 (s, 1H), 7.07 (d, J=3.7 Hz, 1H), 7.03 (s, 1H), 6.97 (d,J=3.7 Hz, 1H), 6.20 (s, 1H), 4.48 (d, J=6.3 Hz, 2H), 1.47 (s, 9H) ppm.

Example 85—Preparation of Compound 60

The synthesis of Compound 60 followed General Procedure 14 following:

To a solution of 6-bromo-4-(5-(((5-chlorothiophen-2-yl) methyl)amino)-1H-pyrazol-3-yl) pyridin-2-ol (Compound 58, 300 mg, 0.77 mmol,1.0 eq) in a mixture of dioxane (2 mL) and water (1.0 mL) was addedpotassium carbonate (K₂CO₃, 215 mg, 1.5 mmol, 2.0 eq), vinyl boronicacid (0.203 g, 1.3 mmol, 1.7 eq). The mixture was then degassed undernitrogen flow for 15 minutes. To this mixture was added1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride(PdCl₂(dppf), 56 mg, 0.07 mmol, 0.1 eq), and the reaction was stirred at80° C. for 12 hours. Product formation was monitored by LC-MS. After themixture was cooled to room temperature, it was diluted with water (5 mL)and extracted with ethyl acetate (25 mL×3). The combined organic layerswere dried over sodium sulfate and concentrated under vacuum. Theresidue was purified by Combi-flash chromatography using hexane:ethylacetate as mobile phase to obtain desire product (130 mg, yield—43.3%)m/z 333.40 [M−H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 12.45-12.21 (m, 1H), 11.52(s, 1H), 6.92 (dd, J=20.0, 9.6 Hz, 2H), 6.68 (d, J=5.1 Hz, 1H), 6.50(dd, J=20.7, 14.4 Hz, 2H), 6.21 (d, J=17.8 Hz, 1H), 6.03 (s, 1H), 5.51(d, J=11.0 Hz, 1H), 4.36 (s, 2H) ppm.

Example 86—Preparation of Compound 61

The synthesis of Compound 61 followed General Procedure 6 following:

To a cold (0° C.) solution of 2-methoxybenzoic acid (93 mg, 0.61 mmol,1.7 eq) in THF (4.0 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl,103 mg, 0.54 mmol, 1.5 eq) and DIPEA (93 mg, 0.72 mmol, 2 eq) and thenstirred at 0° C. for 30 minutes. Compound 60 (120 mg, 0.31 mmol, 1 eq)and HOBT (63 mg, 0.036 mmol, 0.1 eq) were and the reaction mixturestirred for 10-12 hours at room temperature. The completion of reactionwas confirmed by LC-MS. The reaction mixture was diluted with cold water(5.0 mL) and product was extract by using ethyl acetate (3×5 mL). Theorganic phases were dried over sodium sulfate and evaporated undervacuum. The residue was purified by preparative HPLC using water:MeCN asmobile phase to obtained desired product (15 mg, yield—16.7%) m/z 467.57[M−H]+ ¹H NMR (DMSO-d₆) δ 11.67 (s, 1H), 7.58-7.47 (m, 1H), 7.46 (dd,J=7.6, 1.7 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.93(d, J=3.7 Hz, 1H), 6.85 (s, 1H), 6.65 (d, J=3.7 Hz, 1H), 6.47-6.34 (m,1H), 6.27 (s, 1H), 6.06 (d, J=17.8 Hz, 1H), 5.46 (d, J=11.3 Hz, 1H),4.00 (s, 2H), 3.77 (s, 3H) ppm.

Example 87—Preparation of Compound 62

The synthesis of Compound 62 followed General Procedure 14 following:

To a solution of6-bromo-4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 58, 300 mg, 0.77 mmol, 1.0 eq) in a mixture of dioxane andwater (2.0 mL:1.0 mL) was added potassium carbonate (K₂CO₃, 215 mg, 1.5mmol, 2.0 eq), followed by 3-pyridineboronic acid (0.161 g, 1.3 mmol,1.7 eq). The reaction mixture was degassed with a nitrogen stream for 15minutes. The mixture was then degassed under nitrogen flow for 15minutes. To this mixture was the added1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride(PdCl₂(dppf), 56 mg, 0.07 mmol, 0.1 eq), and the reaction was stirred at80° C. for 12 hours. The reaction was monitored by LC-MS. Aftercompletion the reaction mixture was cooled to room temperature. Thereaction mixture was diluted with water (5.0 mL) and extracted withethyl acetate (25 mL×3). The combined organic layers were dried oversodium sulfate and concentrated under vacuum. The residue was purifiedby Combi-flash chromatography using hexane:ethyl acetate as mobile phaseto obtain desire product (60 mg, yield—20%) m/z 384.41 [M−H]+ ¹H NMR(DMSO-d₆, 400 MHz) δ 12.47-12.28 (m, 1H), 8.66 (s, 1H), 8.23 (s, 1H),7.53 (s, 1H), 6.95 (s, 1H), 6.74 (s, 1H), 6.30-6.15 (m, 1H), 6.10-5.98(m, 1H), 4.37 (d, J=6.7 Hz, 2H) ppm.

Example 88—Preparation of Compound 63

The synthesis of Compound 63 followed General Procedure 6 following:

To a cooled solution (0° C.) of 2-furoic acid (40 mg, 0.14 mmol, 1.5 eq)in THF (4.0 mL) was added DIPEA (26 mg, 0.2 mmol, 2 eq) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 50 mg, 0.15 mmol, 1.5 eq). The reaction mixture was stirred for30 minutes. To this was then added Compound 62 (40 mg, 0.15 mmol, 1 eq)and the reaction stirred for 10-12 hours at room temperature. Thereaction was monitored by LC-MS. After completion, the reaction mixturewas diluted with cold water (5.0 mL) and product extracted with ethylacetate (3×5 mL). The combined organic phases were dried over sodiumsulfate and evaporated under vacuum. The residue was purified bypreparative HPLC using water:MeCN as mobile phase to obtained desiredproduct (5 mg, yield—12.5%) m/z 478.57 [M−H]+ ¹H NMR (DMSO-d₆) δ12.51-12.20 (m, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 8.19 (s,1H), 8.10 (d, J=3.5 Hz, 1H), 7.70 (s, 1H), 7.26 (s, 2H), 7.05-6.94 (m,1H), 6.91 (d, J=3.7 Hz, 1H), 6.83 (dd, J=3.5, 1.7 Hz, 1H), 6.78 (s, 1H),6.69 (d, J=3.7 Hz, 1H), 4.10 (s, 2H) ppm.

Example 89—Preparation of Intermediate 25

The synthesis of Intermediate 25 followed General Procedure 1 following.

To a cooled solution (0° C.) of 5-bromopyridine-2-carboxylic acid (50.0g, 0.247 mol, 1.0 eq) in anhydrous methanol (400 mL) was added thionylchloride (107.0 mL, 2.47 mol, 10.0 eq) dropwise. The reaction mixturewas slowly brought to ambient temperature and then heated at 50° C. for12 hours. The reaction was monitored by TLC and LC-MS. After completion,the reaction mixture was concentrated under reduced pressure to obtain awhite solid residue, which was slowly quenched with saturated sodiumbicarbonate. The white solid was filtered to give desired productmethyl-5-bromopyridine-2-carboxylate (43.0 g, yield—80%) m/z 216.14; ¹HNMR (400 MHz, DMSO) δ 8.86 (d, J=1.9 Hz, 1H), 8.28 (dd, J=8.4, 2.4 Hz,1H), 8.00 (d, J=8.4 Hz, 1H), 3.89 (s, 3H) ppm.

Example 90—Preparation of Intermediate 26

The synthesis of Intermediate 26 followed General Procedure 18following.

General Procedure 18

To a cooled solution (0° C.) of methyl-5-bromopyridine-2-carboxylate(Intermediate 25, 20.0 g, 92.6 mmol, 1.0 eq) in dichloromethane (200mL), was added m-CPBA (24.0 g, 139 mmol, 1.5 eq) portionwise. Thereaction mixture was slowly brought to ambient temperature and stirredfor 12 hours. After completion (monitored by TLC and LC-MS), thereaction mixture was concentrated under reduced pressure to obtain awhite solid residue, which was slowly quenched with saturated sodiumbicarbonate and extracted with ethyl acetate. The crude compound waspurified by column chromatography using silica gel (silica 60-120 meshsize), eluting with dichloromethane:methanol (5%-8% gradient) to givethe desire product 5-bromo-2-(methoxycarbonyl)pyridine-1-oxide (12.52 g,yield—58.4%) m/z 234.11 [M+2]⁺; ¹H NMR (400 MHz, CDCl3) δ 8.42 (d, J=1.6Hz, 1H), 7.61-7.51 (m, 1H), 7.47-7.39 (m, 1H), 3.98 (s, 3H) ppm.

Example 91—Preparation of Intermediate 27

The synthesis of Intermediate 27 followed General Procedure 19following.

General Procedure 19

To a cooled solution (0° C.) of5-bromo-2-(methoxycarbonyl)pyridine-1-oxide (Intermediate 26, 2.0 g,8.62 mmol, 1.0 eq) in anhydrous 1,2-dichloroethane (10 mL) was addedphosphorous oxychloride (3.15 mL, 34.5 mmol, 4.0 eq) dropwise. Thereaction mixture was slowly brought to ambient temperature and thenstirred at 50° C. for 12 hours. After completion (monitored by TLC andLC-MS), the reaction mixture was concentrated under reduced pressure.The residue was slowly quenched with aqueous saturated sodiumbicarbonate, and the solid was filtered to give desire productmethyl-5-bromo-6-chloropyridine-2-carboxylate (1.55 g, yield—71.8%) m/z252.17; ¹H NMR (400 MHz, DMSO) δ 8.78 (d, J=2.5 Hz, 1H), 8.50 (d, J=2.5Hz, 1H), 3.89 (s, 3H) ppm.

Example 92—Preparation of Intermediate 28

The synthesis of Intermediate 28 followed General Procedure 20following.

General Procedure 20

To a dry round-bottomed flask pre-cooled to 0° C. and under N₂ gas flow,NaH (0.56 g, 14.0 mmol, 3.5 eq) was added. To this was slowly addedmethoxyethanol (10.0 mL) dropwise, and the mixture was stirred for 30minutes. To this was added methyl-5-bromo-6-chloropyridine-2-carboxylate(Intermediate 27, 1.0 g, 4.0 mmol, 1.0 eq) portionwise. The reactionmixture was then stirred at ambient temperature and then heated at 100°C. for 10 minutes. After completion (monitored by TLC and LC-MS), thereaction mixture was concentrated under reduced pressure to obtain abrown solid residue, which was slowly quenched with acetic acid. Themixture was extracted with 10% MeOH:dichloromethane, dried over sodiumsulfate and concentrated to give the desired product5-bromo-6-(2-methoxyethoxy) pyridine-2-carboxylic acid (Intermediate 28,0.70 g, yield—63%) m/z 278.28 [M+2]⁺; ¹H NMR (400 MHz, DMSO) δ 13.41 (s,1H), 8.19 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 4.52 (dd, J=5.4,3.8 Hz, 2H), 3.71 (dd, J=5.4, 3.8 Hz, 2H), 3.33 (s, 3H) ppm.

Example 93—Preparation of Intermediate 29

The synthesis of Intermediate 29 followed General Procedure 1 following.

To a cooled solution (0° C.) of5-bromo-6-(2-methoxyethoxy)pyridine-2-carboxylic acid (Intermediate 28,3.2 g, 11.6 mmol, 1.0 eq) in anhydrous dichloromethane (40 mL) was addedoxalyl chloride (1.50 mL, 17.4 mmol, 1.5 eq) dropwise. To this was addedanhydrous DMF (0.2 mL), and the reaction mixture was slowly brought toambient temperature and then stirred for 12 hours. After completion, asmonitored by TLC and LC-MS, the mixture was cooled back to 0° C., andanhydrous MeOH (10.0 mL) was added dropwise and stirred for 10-15minutes. The reaction mixture was concentrated under reduced pressure toobtain a white solid residue, which was slowly quenched with saturatedsodium bicarbonate and filtered to give the desired productmethyl-5-bromo-6-(2-methoxyethoxy)pyridine-2-carboxylate (Intermediate29, 3.0 g, yield—89.2%) m/z 292.28 [M+2]⁺; ¹H NMR (400 MHz, CDCl3) δ8.01-7.88 (m, 1H), 7.60 (d, J=7.8 Hz, 1H), 4.72-4.59 (m, 2H), 3.96 (s,3H), 3.87-3.78 (m, 2H), 3.48 (s, 3H) ppm.

Example 94—Preparation of Intermediate 30

The synthesis of Intermediate 30 followed General Procedure 2 following.

To a cooled solution (−78° C.) of acetonitrile (1.3 mL, 23.45 mmol, 1.7eq) in anhydrous THF (75 mL) was added n-BuLi (2.5M in hexane, 9.4 mL,23.45 mmol, 1.7 eq) dropwise over a period of 60 minutes. The reactionwas stirred for a further 60 minutes thereafter. To this was then addeda solution of methyl-5-bromo-6-(2-methoxyethoxy)pyridine-2-carboxylate(Intermediate 29, 4.0 g, 13.8 mmol, 1.0 eq) in THF (20 mL), and thesolution stirred for a further 3 hours. The reaction mixture wasquenched with saturated ammonium chloride solution and product wasextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography using (60-120 mesh size) silica gel,eluting with 0-40% ethyl acetate in n-hexane as mobile phase to givepure desired product5-bromo-6-(2-methoxyethoxy)pyridine-2-oxopropanenitrile (Intermediate30, 3.8 g, yield—92%) m/z 299.19; ¹H NMR (400 MHz, CDCl3) δ 8.14-7.98(m, 1H), 7.61 (d, J=7.8 Hz, 1H), 4.71-4.40 (m, 2H), 4.22 (s, 2H),3.97-3.73 (m, 2H), 3.50 (s, 3H) ppm.

Example 95—Preparation of Compound 64

The synthesis of Compound 64 followed General Procedure 3 following.

To a solution of 5-bromo-6-(2-methoxyethoxy)pyridine-2-oxopropanenitrile (Intermediate 30, 8.0 g, 27 mmol, 1.0 eq) in isopropanol (125mL) and acetic acid (0.8 mL, 13.4 mmol, 0.5 eq) was added hydrazinemonohydrate (0.8 g, 40.5 mmol, 1.5 eq) dropwise. The reaction wasstirred at 65° C. for 5 hours. After completion (monitored by TLC andLC-MS), the reaction mixture was concentrated under reduced pressure.The residue was purified by column chromatography using silica gel(60-120 mesh), eluting with 5% MeOH:dichloromethane to give desiredproduct 3-(5-bromo-6-(2-methoxyethoxy)pyridin-2-yl)-1H-pyrazol-5-amine(Compound 64, 8.0 g, yield—94.7%) m/z 314.92; ¹H NMR (400 MHz, C6D6) δ7.22 (d, J=7.8 Hz, 1H), 6.95 (s, 3H), 6.45 (t, J=11.9 Hz, 1H), 5.59 (s,1H), 4.39 (dd, J=15.4, 10.6 Hz, 2H), 3.48-3.50 (m, 2H), 3.14 (s, 3H)ppm.

Example 96—Preparation of Compound 65

The synthesis of Compound 65 followed General Procedure 17 following:

To a round-bottomed flask charged with3-(5-bromo-6-(2-methoxyethoxy)pyridin-2-yl)-1H-pyrazol-5-amine (1.6mmol) was added concentrated hydrochloric acid (5 mL). The mixture washeated at 120° C. for 6 hrs. The excess of HCl-water was evaporatedunder vacuum and the crude mass was quenched with sodium bicarbonatesolution. The reaction mixture was extracted with ethyl acetate (3times). The combined organic mass was dried over sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography using (60-120 mesh size) silica gel, eluting with neatmethanol as mobile phase to give pure desired product6-(5-amino-1H-pyrazol-3-yl)-3-bromopyridin-2(1H)-one (Compound 65, 0.220g, yield—48.9%) m/z 255.34 [M+1]+; ¹H NMR (400 MHz, DMSO) δ 11.94 (s,2H), 7.90 (d, J=7.6 Hz, 1H), 6.54 (d, J=7.4 Hz, 1H), 5.98 (s, 1H), 5.20(s, 2H) ppm.

Example 97—Preparation of Compound 66

The synthesis of Compound 66 followed General Procedure 4 following:

To a cooled solution (0-10° C.) of3-(5-amino-1H-pyrazol-3-yl)-5-methylpyridin-2(1H)-one (Compound 65,0.200 g, 0.78 mmol, 1.0 eq) in methanol (5 mL) was added acetic acid(0.046 g, 0.78 mmol, 1.0 eq) dropwise. To this was added5-chlorothiophene-2-carbaldehyde (0.137 g, 0.93 mmol, 1.2 eq) dropwise,and the mixture was stirred for another 30-45 minutes at roomtemperature. Sodium cyanoborohydride (0.073 g, 1.17 mmol, 1.5 eq) wasadded portionwise over a period of 15 minutes. The reaction was stirredfor 3 hours. After completion of reaction, the mixture was poured intoice cold water under stirring, and extracted with ethyl acetate. Theorganic phases were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing silica gel, eluting with 10-100% methanol in dichloromethane togive pure desired product3-bromo-6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 66, 0.250 g, yield—82.7%) m/z 387.08 [M+1]+; ¹H NMR (400 MHz,DMSO) δ11.84 (s, 1H), 7.47 (s, 1H), 6.92 (d, J=3.7 Hz, 1H), 6.87 (d,J=3.7 Hz, 1H), 6.25 (s, 1H), 5.85 (s, 1H), 4.33 (d, J=6.1 Hz, 2H) ppm.

Example 98—Preparation of Compound 67

The synthesis of Compound 67 followed General Procedure 6 following:

To a dry, cooled solution (0° C.) of furan-3-carboxylic acid (0.0014 g,0.121 mmol, 1 eq) in THF (2 mL) was added EDCI.HCl (0.027 g, 0.14 mmol,1.2 eq), followed by triethylamine (0.036 g, 0.36 mmol, 3.0 eq). Thereaction mixture was stirred for 30 minutes, and then to it was addedhydroxybenzotriazole (HOBt, 3.2 mg, 0.024 mmol, 0.2 eq), followed by3-bromo-6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 66, 0.05 g, 0.121 mmol, 1.0 eq). After completion (monitoredby LC-MS), the reaction mixture was poured into water (10 mL) andextracted with ethyl acetate. The combined organic phases were washedwith water, then brine, and dried over sodium sulfate. After evaporationunder reduced pressure, the residue was purified by preparative HPLCusing water-acetonitrile as mobile phase to give desired product3-bromo-6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 67, 6.4 mg, yield—12.9%) m/z 481.42 [M+1]+ 1H NMR (400 MHz,DMSO) δ 12.35-12.25 (m, 1H), 9.39 (s, 1H), 8.07 (s, 1H), 8.02 (d, J=7.6Hz, 1H), 7.93-7.87 (m, 1H), 7.13-7.02 (m, 2H), 6.98 (d, J=3.8 Hz, 1H),6.82-6.74 (m, 1H), 6.26 (s, 1H), 4.53 (d, J=6.5 Hz, 2H) ppm.

Example 99—Preparation of Intermediate 31

The synthesis of Intermediate 31 followed General Procedure 1 following:

To a cooled solution (0° C.) of 6-hydroxynicotinic acid (25.0 g, 179mmol, 1.0 eq) in methanol (375 mL) was added thionyl chloride (107 g.899 mmol, 5.0 eq) dropwise. The reaction mixture was heated at refluxfor 12 hours. After completion, the reaction mixture was cooled back toroom temperature and then concentrated under reduced pressure. Theresidue was diluted with methanol and concentrated under vacuum. Theresidue was washed with hexane and ethyl acetate and dried under vacuumto obtain white a solid compound (Intermediate 31, 27.51 g yield—91.9%)m/z [M+H]+ 154.2. ¹H NMR (DMSO-d₆) δ 12.15 (s, 1H), 8.05 (d, J=2.5 Hz,1H), 7.80 (dd, J=9.6, 2.7 Hz, 1H), 6.37 (d, J=9.6 Hz, 1H), 3.77 (s, 3H)ppm.

Example 100—Preparation of Intermediate 32

The synthesis of Intermediate 32 followed General Procedure 2 following.

To a cooled solution (−78° C.) of acetonitrile (8.2 mL, 156 mmol, 1.2eq) in tetrahydrofuran (300 mL) was added ^(n)BuLi (2.5M in hexane, 62.7mL, 156 mmol, 1.2 eq) dropwise over a period of 60 minutes, and reactionwas stirred for another 60 minutes thereafter. To this was added methyl6-oxo-1,6-dihydropyridine-3-carboxylate (Intermediate 31, 20.0 g, 130mmol, 1.0 eq) portionwise, and the reaction mixture was maintained at−78° C. for a further 3 hours. After completion, the reaction mixturewas quenched with ammonium chloride solution and extracted with ethylacetate. The organic layer was evaporated to obtain crude product, whichwas suspended in methanol and stirred for 30 minutes at roomtemperature. The solid was filtered through suction and dried under highvacuum to yield the desired Intermediate 32 (11.5 g, yield—58%) m/z162.74 [M+H]+.

Example 101—Preparation of Compound 68

The synthesis of Compound 68 followed General Procedure 3 following.

To a solution of 3-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)propanenitrile(Intermediate 32, 20.0 g, 123 mmol, 1.0 eq) in isopropanol (600 mL) wasadded acetic acid (22.2 mL). To this was added hydrazine monohydrate(7.40 mL, 148 mmol, 1.2 eq) dropwise. The reaction mixture was thenstirred at 85° C. for 5 hours. After completion, the reaction mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography using neutral silica gel (60-120 mesh), elutingwith 10-25% methanol in dichloromethane as gradient to give the desiredproduct (Compound 68, 13.25 g, yield—61%) m/z [M+H]+ 176.9 ¹H NMR (400MHz, DMSO-d₆) δ 11.31 (s, 2H), 7.75 (dd, J=9.5, 2.6 Hz, 1H), 7.63 (d,J=2.1 Hz, 1H), 6.37 (d, J=9.5 Hz, 1H), 5.58 (s, 1H), 4.82 (s, 2H) ppm.

Example 102—Preparation of Compound 69

The synthesis of Compound 69 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of5-(5-amino-1H-pyrazol-3-yl)pyridin-2(1H)-one (Compound 68, 56.7 mmol) inmethanol (100 mL) was added acetic acid (11.2 mL) dropwise. To this wasadded 5-chlorothiophene-2-carbaldehyde (9.15 g, 62.4 mmol, 1.1 eq)portionwise, and the reaction mixture was stirred for a further 45minutes at room temperature. Sodium cyanoborohydride (5.35 g, 85.1 mmol,1.5 eq) was then added portionwise over a period of 45 minutes and themixture was stirred for 2 hours. After reaction completion, the mixturewas poured into ice cold water under stirring and extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography using neutral silica gel, eluting with 10-12% methanol indichloromethane to give pure desired product (Compound 69, 7.3 g,yield—42.7%) m/z [M+H]+ 307.00 ¹H NMR (DMSO-d₆) δ 11.77 (s, 2H), 7.73(d, J=9.5 Hz, 1H), 7.68 (s, 1H), 6.96-6.90 (m, 1H), 6.88 (d, J=3.6 Hz,1H), 6.39 (d, J=9.5 Hz, 1H), 5.95 (s, 1H), 5.75 (s, 1H), 4.33 (d, J=6.3Hz, 2H) ppm.

Example 103—Preparation of Compound 70

The synthesis of Compound 70 followed General Procedure 6 following:

To a cooled solution (0-5° C.) of thiophene-3-carboxylic acid (0.602 g,1.2 eq, 4.71 mmol) in dimethylformamide (20.0 mL) was added EDCI.HCl(0.903 g, 1.2 eq, 4.71 mmol), and DIPEA (0.606 g, 1.2 eq, 4.71 mmol).After stirring at 0-5° C. for 30 minutes, to the mixture was addedCompound 69 (1.2 g, 1.0 eq, 3.9 mmol) and HOBt (0.105 g, 0.2 eq, 0.784mmol), and the mixture stirred for 14 hours at room temperature. Thereaction was monitored by LCMS. After completion, the mixture was pouredinto ice cold water under stirring and extracted with ethyl acetate(3×25 mL). The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel (100-200 mesh) in the presence of 0.05%triethylamine, eluting with 20-25% ethyl acetate in n-hexane to givepure desired product (Compound 70, 0.98 g, yield=60.1%) m/z 417.23[M+1]+ ¹H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 9.13-9.01 (m, 1H), 7.98(ddd, J=19.9, 11.5, 4.8 Hz, 3H), 7.82 (dd, J=5.1, 1.1 Hz, 1H), 7.67 (dd,J=5.1, 3.0 Hz, 1H), 7.07 (d, J=3.7 Hz, 1H), 6.98 (d, J=3.7 Hz, 1H), 6.44(d, J=9.6 Hz, 1H), 6.09 (s, 1H), 4.53 (d, J=6.3 Hz, 2H) ppm.

Example 104—Preparation of Compound 71

The synthesis of Compound 71 followed General Procedure 6 following:

To a cooled solution (0-5° C.) of pivalic acid (0.395 g, 1.2 eq, 3.9mmol) in dimethylformamide (20.0 mL) was added EDCI.HCl (0.749 g, 1.2eq, 3.9 mmol) and DIPEA (0.842 g, 2.0 eq, 6.5 mmol). After stirring for30 minutes, to the reaction mixture was added Compound 69 (1.0 g, 1.0eq, 3.3 mmol), followed by HOBt (0.119 g, 0.2 eq, 0.784 mmol). Thereaction was stirred for 14 hours at room temperature. The reaction wasmonitored by LCMS. After completion, the mixture was poured into icecold water under stirring and extracted with ethyl acetate (3×20 mL).The organic phase was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing silica gel (100-200 mesh) in the presence of 0.05% triethylamine,eluting with 25-30% ethyl acetate in n-hexane as mobile phase to givepure desired product (Compound 71, 0.8 g, yield=62.8%) m/z 391.28 [M+1]+¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 7.94-7.71 (m, 3H), 7.04 (d,J=3.7 Hz, 1H), 6.97 (d, J=3.8 Hz, 1H), 6.45 (d, J=9.7 Hz, 1H), 5.95 (s,1H), 4.46 (d, J=5.7 Hz, 2H), 1.45 (s, 9H) ppm.

Example 105—Preparation of Compound 72

The synthesis of Compound 72 followed the procedure of General Procedure8 following.

To a solution of Compound 71 (0.4 g, 1.0 eq, 1.03 mmol) in DMF (15 mL)was added anhydrous cesium carbonate (0.839 g, 2.5 eq, 2.6 mmol),followed by the addition of 4-chloroacetyl morpholine (0.252 g, 1.2 eq,1.54 moles). The reaction mixture was stirred for 12 hours at roomtemperature. After completion (monitored by TLC and LCMS), the reactionmixture was poured into ice cold water under stirring and extracted withethyl acetate (3×25 mL). The organic layer was dried over sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography using neutral silica gel, eluting with 60-65%ethyl acetate in n-hexane as mobile phase to give pure desired product(Compound 72, 0.065 g, yield=12.7%). m/z 518.31 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 8.08 (d, J=2.3 Hz, 1H), 7.98-7.81 (m, 2H), 6.99 (dd, J=7.5, 3.8Hz, 2H), 6.52 (d, J=9.4 Hz, 1H), 5.79 (s, 1H), 4.89 (s, 2H), 4.47 (d,J=6.2 Hz, 2H), 3.67 (s, 2H), 3.59 (d, J=5.2 Hz, 4H), 3.46 (s, 2H), 1.47(s, 9H) ppm.

Example 106—Preparation of Intermediate 33

The synthesis of Intermediate 33 followed General Procedure 1 following.

To a room temperature solution of commercially available6-hydroxypicolinic acid (20.0 g, 143 mmol, 1.0 eq) in methanol (200 mL)was slowly added thionyl chloride (84.89 g, 710 mmol, 5.0 eq). Thereaction mixture was heated to reflux overnight. After completion, thereaction mixture was concentrated under reduced pressure. The residuewas washed with ethyl acetate and dried under vacuum to give the desiredcompound 6-hydroxypicolinic acid, methyl ester (Intermediate 33, 20.0 g,yield—90%) m/z [M+1]+ 154.15.

Example 107—Preparation of Intermediate 34

The synthesis of Intermediate 34 followed General Procedure 2 following.

To a dry (N₂ gas flow) and cooled solution (−78° C.) of acetonitrile(4.01 g, 98 mmol, 1.5 eq) in tetrahydrofuran (150 mL) was added ^(n)BuLi(2.5 M in hexane, 39.2 mL, 98 mmol, 1.5 eq) dropwise over a period of 60minutes. The reaction was stirred for another 60 minutes thereafter.6-Hydroxypicolinic acid, methyl ester (Intermediate 33, 10.0 g, 65.4mmol, 1.0 eq.) was added portionwise to the reaction mixture and thetemperature maintained at −78° C. for 3 hours. The reaction progress wasmonitored by LCMS. After completion, the reaction mass was quenched withethyl acetate and the mixture concentrated under reduced pressure. Theresidue was triturated with diethyl ether and dried under reducedpressure to obtain desired product3-oxo-3-(6-oxo-1,6-dihydropyridin-2-yl)propanenitrile (Intermediate 34)which was used as such for the next step (6.0 g, yield—56.3%) m/z [M+1]+163.07.

Example 108—Preparation of Compound 73

The synthesis of Compound 73 followed General Procedure 3 following.

To a solution of 3-oxo-3-(6-oxo-1,6-dihydropyridin-2-yl)propanenitrile(Intermediate 34, 10.0 g, 61 mmol, 1.0 eq) in isopropanol (300 mL) wasadded acetic acid (3.7 mL, 61 mmol, 1.0 eq), followed by dropwiseaddition of hydrazine monohydrate (3.37 g, 67 mmol, 1.1 eq). Thereaction was then stirred at 80° C. for 4 hours. The reaction progresswas monitored by LCMS. After completion, the reaction mixture wasconcentrated under vacuum. The residue was purified by columnchromatography using silica gel (100-200 mesh), eluting with 5% methanolin dichloromethane as gradient to give desired product6-(5-amino-1H-pyrazol-3-yl)pyridin-2(1H)-one (Compound 73, 1.0 g,yield—62.1%) m/z [M+1]+ 177.12. ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s,1H), 11.06 (s, 1H), 7.44 (s, 1H), 6.57 (s, 1H), 6.25 (s, 1H), 5.91 (s,1H), 5.19 (s, 2H) ppm.

Example 109—Preparation of Compound 74

The synthesis of Compound 74 followed General Procedure 4 following:

To a cooled solution (10-15° C.) of6-(5-amino-1H-pyrazol-3-yl)pyridin-2(1H)-one (Compound 73, 1.0 g, 5.7mmol, 1.0 eq) in methanol (20 mL) was added acetic acid (0.34 g, 5.7mmol, 1.0 eq), followed by portionwise addition of5-chlorothiophene-2-carbaldehyde (0.915 g, 6.3 mmol, 1.1 eq). Thereaction was allowed to stir for 2-3 hours at room temperature. To thereaction mixture was then added sodium cyanoborohydride (0.078 g, 12.5mmol, 2.0 eq) portionwise over a period of 15 minutes. The reaction wasthen stirred for 12 hours at room temperature. After completion, thereaction mixture was diluted in ice cold water and extracted with ethylacetate (3×30 mL). The organic layers were combined and dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography using silica gel (60-120mesh), eluting with 60% ethyl acetate in hexane as mobile phase to givepure desired product (Compound 74, 0.2 g, yield—9.1%) m/Z 307.1 [M+1]H+¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 11.58 (s, 1H), 7.47 (s, 1H),6.94 (t, J=9.7 Hz, 2H), 6.59 (s, 1H), 6.28 (s, 3H), 4.34 (d, J=6.1 Hz,2H) ppm.

Example 110—Preparation of Compound 75

The synthesis of Compound 75 followed General Procedure 6 following:

To a cooled solution (0° C.) of pivalic acid (0.25 g, 2.4 mmol, 1.5 eq)in DMF (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI.HCl, 0.47 g, 2.5 mmol, 1.5 eq), hydroxybenzotriazole(HOBt, 0.043 g, 0.33 mmol, 0.2 eq) and N,N-diisopropylethylamine (DIPEA,0.231 g, 1.8 mmol, 1.1 eq). The reaction mixture was allowed to stir at0° C. for 20 minutes and to it was then added6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one (Compound 74, 0.5 g, 1.6 mmol,1.0 eq). The reaction mixture was stirred at room temperature for 12hours. After completion of reaction, the mixture was diluted with waterand extracted with ethyl acetate (3×20 mL). The combined organic phaseswere dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by column chromatography using silica (100-200silica), eluting with 60% ethyl acetate in hexane, yielding desiredproduct6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 75, 0.124 g, yield: 19.9%); m/z [M+1]+ 391.24 ¹H NMR (400 MHz,DMSO) δ 11.37 (s, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.01 (dd, J=14.3, 3.6Hz, 2H), 6.46 (s, 1H), 6.12 (s, 1H), 4.47 (d, J=6.0 Hz, 2H), 1.47 (s,9H) ppm.

Example 111—Preparation of Compound 76

The synthesis of Compound 76 followed the procedure of General Procedure8 following.

To a solution of6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 75, 0.07 g, 1.0 eq, 0.18 mmol) in DMF (1.5 mL) was addedanhydrous cesium carbonate (0.146 g, 2.5 eq, 4.5 mmol). The reaction wasstirred for 10 minutes, followed by the addition of 4-chloroacetylmorpholine (0.44 g, 1.5 eq, 0.27 mmol). The reaction mixture was stirredfor 30 minutes at room temperature. The reaction was monitored by TLC.After completion, the reaction mass was poured onto ice cold water understirring and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing (60-120) mesh silica gel in presence of 0.05% trimethylamine,eluting with 60% ethyl acetate in n-hexane as mobile phase, yieldingdesired product6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(1H)-one(Compound 76, 0.054 g, yield: 58.7%); m/z 518.39 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 7.90 (s, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H),6.98 (s, 2H), 6.91 (d, J=8.4 Hz, 1H), 5.87 (s, 1H), 5.11 (s, 2H), 4.52(d, J=5.5 Hz, 2H), 3.62 (s, 2H), 3.53 (s, 4H), 3.39 (s, 2H), 1.49 (s,9H) ppm.

Example 112—Preparation of Compound 77

The synthesis of Compound 77 followed the procedure of General Procedure8 following:

To a dry solution of6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 75, 0.309 g, 2.5 eq, 9.5 mmol) in dimethylformamide (5.0 mL)was added 2-(chloromethyl)pyridine hydrochloride (0.93 g, 1.5 eq, 0.6mmol), followed by cesium carbonate and stirred for 16 hours at roomtemperature. The reaction was monitored by TLC and LCMS. Aftercompletion the reaction mass was poured into ice cold water understirring and product was extracted with ethyl acetate (3×20 mL). Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing (60-120) mesh silica gel in presence of 0.05% trimethylamine,eluting with 10-20% ethyl acetate in n-hexane as mobile phase to givepure desired product6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one(Compound 77, 0.0272 g, yield: 14.6%) m/z=482.51 [M+1]+ ¹H NMR (400 MHz,DMSO-d₆) δ 8.57 (d, J=4.8 Hz, 1H), 7.90-7.73 (m, 3H), 7.58 (d, J=7.4 Hz,1H), 7.48 (d, J=7.8 Hz, 1H), 7.38-7.24 (m, 1H), 7.07-6.83 (m, 3H), 5.91(s, 1H), 5.51 (s, 2H), 4.52 (d, J=6.2 Hz, 2H), 1.48 (s, 9H) ppm.

Example 113—Preparation of Compound 78

The synthesis of Compound 78 followed General Procedure 14 following:

To a solution of6-bromo-4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 58, 0.2 g, 0.51 mmol, 1.0 eq) and phenylboronic acid (0.063 g,0.51 mmol, 1.0 eq) in dioxane:water (5:1, 10 mL) was added potassiumcarbonate (0.215 g, 1.5 mmol, 3.0 eq). The reaction mixture was degassedunder nitrogen for 30 minutes, and to it was added1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride(PdCl₂(dppf), 0.037 g, 0.05 mmol, 0.1 eq). The reaction mixture wasstirred at 100° C. for 5-6 hours. After completion the reaction mixturewas diluted with water and extracted with dichloromethane (25 mL×3). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography using neutral silica gel (100-200 mesh), eluting with4-5% methanol in dichloromethane as gradient to give pure desiredproduct (Compound 78, 0.12 g, yield—60%) m/z 383.15.05 [M+H]+ ¹H NMR(DMSO-d₆, 400 MHz) δ 12.41 (s, 1H), 11.82 (s, 1H), 7.82 (s, 2H), 7.50(d, J=6.5 Hz, 3H), 6.95 (dd, J=16.0, 12.4 Hz, 3H), 6.65 (s, 1H), 6.16(s, 2H), 4.37 (d, J=6.4 Hz, 2H) ppm.

Example 114—Preparation of Compound 79

The synthesis of Compound 79 followed General Procedure 6 following:

To a solution of thiophene-3-carboxylic acid (0.040 g, 0.31 mmol, 1.2eq) in THF:acetonitrile (1:1; 5 mL) was added N,N-diisopropylethylamine(DIPEA, 0.1 mL, 0.78 mmol, 3 eq), thenN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 0.148 g, 0.39 mmol, 1.5 eq). Themixture was stirred at room temperature for 1 hour. To this was thenadded 4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-6-phenylpyridin-2(1H)-one (Compound 78, 0.2 g,0.51 mmol, 1.0 eq) and stirring continued for 12 hours. Aftercompletion, the reaction mixture was diluted with water and extractedwith dichloromethane (25 mL×3). The organic phase were dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by preparative HPLC to give pure desired product (Compound 79,30 mg, yield: 33%) m/z 493.2 [M+H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 12.43(d, J=132.0 Hz, 1H), 8.72 (s, 1H), 8.36-8.03 (m, 3H), 7.78 (d, J=24.4Hz, 1H), 7.75-7.62 (m, 1H), 7.55 (d, J=8.9 Hz, 3H), 7.30-6.67 (m, 3H),6.40 (s, 1H), 6.16 (d, J=37.6 Hz, 1H), 4.40 (d, J=6.2 Hz, 2H) ppm.

Example 115—Preparation of Compound 80

The synthesis of Compound 80 followed General Procedure 14 following:

To a solution of6-bromo-4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 58, 300 mg, 0.77 mmol, 1.0 eq) in dioxane and water (2.0mL:1.0 mL) was added potassium carbonate (K₂CO₃, 215 mg, 1.5 mmoles, 2.0eq), followed by 3-pyridineboronic acid (0.161 g, 1.3 mmol, 1.7 eq). Thereaction mixture was degassed with a stream of nitrogen for 15 minutes.To the reaction was then added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (PdCl₂(dppf), 56 mg, 0.07 mmol, 0.1 eq), andthe reaction was stirred at 80° C. for 12 hours. The reaction wasmonitored by LC-MS and after completion the reaction mixture was cooledto room temperature. The reaction mixture was diluted with water (5 mL)and extracted with ethyl acetate (25 mL×3). The combined organic layerswere dried over sodium sulfate and concentrated under vacuum. Theresidue was purified by Combi-flash chromatography using hexane:ethylacetate as mobile phase to obtain desired product (Compound 80, 60 mg,yield—20%) m/z 384.41 [M−H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ 12.47-12.28 (m,1H), 8.66 (s, 1H), 8.23 (s, 1H), 7.53 (s, 1H), 6.95 (s, 1H), 6.74 (s,1H), 6.30-6.15 (m, 1H), 6.10-5.98 (m, 1H), 4.37 (d, J=6.7 Hz, 2H) ppm.

Example 116—Preparation of Compound 81

The synthesis of Compound 81 followed General Procedure 6 following:

To a cooled solution (0° C.) of 2-furoic acid (40 mg, 0.14 mmol, 1.5 eq)in THF (4 mL) was added N,N-diisopropylethylamine (DIPEA, 26 mg, 0.2mmol, 2 eq) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU, 50 mg, 0.15 mmol, 1.5 eq). The reaction wasstirred for 30 minutes. Compound 80 (40 mg, 0.15 mmol, 1 eq) was added,and the reaction mixture stirred for 12 hours at room temperature. Thereaction was monitored by LC-MS. After completion, the reaction mixturewas diluted with cold water (5 mL) and extracted with ethyl acetate (3×5mL). The combined organic phases were dried over sodium sulfate andevaporated under vacuum. The residue was purified by preparative HPLCusing water:acetonitrile as mobile phase to obtained desired product(Compound 81, 5 mg, yield: 12.5%) m/z 478.57 [M−H]+ ¹H NMR (DMSO-d₆) δ12.51-12.20 (m, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 8.19 (s,1H), 8.10 (d, J=3.5 Hz, 1H), 7.70 (s, 1H), 7.26 (s, 2H), 7.05-6.94 (m,1H), 6.91 (d, J=3.7 Hz, 1H), 6.83 (dd, J=3.5, 1.7 Hz, 1H), 6.78 (s, 1H),6.69 (d, J=3.7 Hz, 1H), 4.10 (s, 2H) ppm.

Example 117—Preparation of Compound 82

The synthesis of Compound 82 followed General Procedure 14 following:

To a solution of5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 23, 600 mg, 1.03 mmol, 1.0 eq) in a mixture of dioxane (2 mL)and water (1 mL) was added potassium carbonate (K₂CO₃, 286 mg, 2.0 mmol,2.0 eq). Pyridine-3-boronic acid (190 mg, 1.5 mmol, 1.5 eq) was added toreaction mixture and degassed by nitrogen bubbling for 15 minutes. Tothe mixture was then added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (PdCl₂(dppf), 0.1 mmol, 0.1 eq). and thereaction was stirred at 80° C. for 12 hours. Product formation wasmonitored by LC-MS, and on completion the reaction mixture was cooledback down to room temperature. The reaction mixture was diluted withwater (5 mL) and extracted with ethyl acetate (25 mL×3). The combinedorganic layers were dried over sodium sulfate and concentrated undervacuum. The residue was purified by Combi-flash chromatography usinghexane:ethyl acetate as mobile phase to obtain desire product (Compound82, 130 mg, yield: 21.7%) m/z 384.56 [M−H]+ ¹H NMR (DMSO-d₆, 400 MHz) δ12.39 (s, 1H), 11.91 (s, 1H), 8.91 (s, 1H), 8.52 (d, J=4.6 Hz, 1H), 8.32(d, J=2.6 Hz, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.49-7.46 (m,1H), 6.93 (d, J=3.7 Hz, 1H), 6.88 (d, J=3.7 Hz, 1H), 6.34 (s, 1H), 5.90(s, 1H), 4.37 (d, J=6.3 Hz, 2H) ppm.

Example 118—Preparation of Compound 83

The synthesis of Compound 83 followed General Procedure 6 following:

To a cooled solution (0° C.) of 2-methoxybenzoic acid (120 mg, 0.46mmol, 1.5 eq) in THF (4.0 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl,89 mg, 0.46 mmol, 1.5 eq), followed by N,N-diisopropylethylamine (DIPEA,80 mg, 0.62 mmol, 2 eq). After stirring at 0° C. for a further 30minutes,5-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-[3,3′-bipyridin]-6(1H)-one(Compound 82, 120 mg, 0.31 mmol, 1 eq) and hydroxybenzotriazole (HOBt,63 mg, 0.46 mmol, 1.5 eq) were added. The reaction mixture was stirredfor 12 hours at room temperature. After completion of reaction, asconfirmed by LC-MS, the reaction mixture was diluted with cold water (5mL), extracted with ethyl acetate (3×5 mL), dried over sodium sulphateand evaporated under vacuum. The residue was purified by preparativeHPLC using Water:acetonitrile as mobile phase (Compound 83, 0.038 g,yield: 25%) m/z 518.68 [M−H]+ 1H NMR (DMSO-d6, 400 MHz) δ 12.32-12.20(m, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.87 (s, 2H), 7.77(s, 1H), 7.59-7.31 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.03 (d, J=15.4 Hz,3H), 6.27 (s, 1H), 4.57 (d, J=6.2 Hz, 2H), 3.77 (s, 3H) ppm.

Example 119—Preparation of Compound 84

The synthesis of Compound 84 followed the procedure of General Procedure21 following:

General Procedure 21

A solution of Compound 18 (0.070 g, 1.0 eq) in MeOH/HCl (1%, 20 mL) wasstirred for 16 hours at room temperature. The reaction was monitored byTLC and LCMS. After completion volatiles were evaporated under reducedpressure, which was purified by prep HPLC to yield Compound 84 (0.0182g, yield: 33%) m/z 398.1 [M]+ ¹H NMR (400 MHz, DMSO) δ 12.35 (s, 1H),8.58 (d, J=1.7 Hz, 1H), 8.49 (dd, J=4.8, 1.5 Hz, 1H), 7.88 (s, 1H), 7.70(d, J=7.9 Hz, 1H), 7.37 (dd, J=7.8, 4.8 Hz, 1H), 6.93 (t, J=6.3 Hz, 2H),6.69 (s, 1H), 6.62 (s, 1H), 6.05 (s, 2H), 5.12 (s, 2H), 4.35 (d, J=6.2Hz, 2H) ppm.

Example 120—Preparation of Compound 85

The synthesis of Compound 85 followed the procedure of General Procedure8 following.

To a solution of Compound 9 (0.11 g, 1.0 eq, 0.28 mmol) in DMF (10 mL)was added anhydrous cesium carbonate (0.178 g, 2.5 eq, 0.55 mmol). Afterstirring for 15 minutes at room temperature, 3-(chloromethyl)pyridinehydrochloride (0.09 g, 2.0 eq, 0.55 mmol) was added and the reaction wasstirred for a further 14 hours at room temperature. The reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with ice cold water under stirring and extracted with ethylacetate (10 mL×3). The organic phases were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to furnish the desired product, Compound 85 (0.018 g,yield: 13.3%) m/z 492.1 [M]+ ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H),8.60 (s, 1H), 8.50 (d, J=3.4 Hz, 1H), 7.94 (d, J=7.0 Hz, 2H), 7.89 (s,1H), 7.72 (d, J=7.4 Hz, 1H), 7.41-7.36 (m, 1H), 7.09 (s, 2H), 7.00-6.92(m, 2H), 6.88 (d, J=6.6 Hz, 1H), 6.26 (s, 1H), 5.18 (s, 2H), 4.55 (d,J=5.9 Hz, 2H) ppm.

Example 121—Preparation of Compound 86

The synthesis of Compound 86 followed the procedure of General Procedure8 following.

To a solution of Compound 13 (0.2 g, 1.0 eq, 513 mmoles) in DMF (10 mL)was added anhydrous cesium carbonate (0.416 g, 2.5 eq, 1.28 mmoles).After stirring for 30 minutes, the at room temperature,(3-chloromethyl)pyridine hydrochloride (0.126 g, 1.2 eq, 0.76 mmol) wasadded, and the reaction mixture stirred for 3 hours at 80° C. Thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was poured into ice cold water under stirring and extracted withethyl acetate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography using 60-120 mesh silica gel in the presence of 0.05%trimethylamine, eluting with 30-35% ethyl acetate in n-hexane, to givepure desired product Compound 86 (0.105 g, yield: 39%) m/z 482.41 [M]+¹H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.51 (s, 1H), 7.95 (d, J=6.8 Hz,1H), 7.87 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.38 (d, J=5.2 Hz, 1H), 7.07(d, J=3.7 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H), 6.87 (s, 1H), 6.72 (d, J=6.5Hz, 1H), 6.14 (s, 1H), 5.14 (d, J=16.4 Hz, 2H), 4.47 (d, J=6.4 Hz, 2H),1.46 (s, 9H) ppm.

Example 122—Preparation of Compound 87

The synthesis of Compound 87 followed the procedure of General Procedure8 following.

To a solution of Compound 9 (0.5 g, 1.0 eq, 1.25 mmol) in DMF (10 mL)was added anhydrous cesium carbonate (1.0 g, 2.5 eq, 3.1 mmol). Afterstirring for 15 minutes at room temperature, 4-(2-chloroethyl)morpholine(0.349 g, 1.5 eq, 1.88 mmol) was added and the reaction was stirred for12 hours at room temperature. The reaction was monitored by TLC andLCMS. The reaction mixture was poured into ice cold water under stirringand extracted with ethyl acetate. The organic layer was dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by preparative HPLC to yield Compound 87 (0.08 g, yield: 12%)m/z [M+H]+ 514.33 ¹H NMR (400 MHz, DMSO) δ 8.94 (d, J=0.7 Hz, 1H), 7.96(t, J=6.3 Hz, 1H), 7.90 (t, J=1.7 Hz, 1H), 7.71 (d, J=7.1 Hz, 1H), 7.10(t, J=3.1 Hz, 2H), 6.97 (d, J=3.7 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J=6.9Hz, 1H), 6.25 (s, 1H), 4.55 (d, J=6.3 Hz, 2H), 4.04 (d, J=5.6 Hz, 2H),3.55 (s, 4H), 2.56 (d, J=5.5 Hz, 2H), 2.43 (s, 4H) ppm.

Example 123—Preparation of Compound 88

The synthesis of Compound 88 followed the procedure of General Procedure8 following.

To a solution of Compound 17 (0.8 g, 1.0 eq, 1.92 mmol) in DMF (15 mL)was added anhydrous cesium carbonate (1.246 g, 2.0 eq, 3.8 mmole). Afterstirring the reaction for 15 minutes at room temperature,4-(2-chloroethyl)morpholine (0.428 g, 1.5 eq, 2.9 mmol) was added andthe reaction stirred for a further 48 hours at room temperature. Thereaction was monitored by TLC and LCMS. After completion the reactionmass was poured into ice cold water under stirring and extracted withethyl acetate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to yield Compound 88 (0.035 g, yield: 4.2%) m/z [M+H]+530.58 ¹H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 7.98 (s, 1H), 7.83 (d,J=4.9 Hz, 1H), 7.72 (d, J=7.5 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.87(s, 1H), 6.74 (d, J=6.2 Hz, 1H), 6.25 (s, 1H), 4.55 (d, J=5.7 Hz, 2H),4.02 (s, 2H), 3.54 (s, 4H), 2.57 (s, 2H), 2.43 (s, 4H) ppm.

Example 124—Preparation of Compound 89

The synthesis of Compound 89 followed General Procedure 6 following:

To a cold solution (0° C.) of thiophene-3-carboxylic acid (0.15 g, 1.2mmol, 1.5 eq) in THF (25 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl,0.224 g, 1.2 mmol, 1.5 eq) and N,N-diisopropylethylamine (DIPEA, 0.2 mL,1.29 mmol, 1.1 eq) under nitrogen. After stirring for 30 minutes,hydroxybenzotriazole (HOBt, 0.021 g, 0.156 mmol, 0.2 eq) and5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one (Compound 23, 0.3 g, 0.78 mmol, 1.0 eq) were added.After completion, (monitored by LC-MS), the reaction mixture was pouredinto water (20 mL) and extracted with ethyl acetate. The combinedorganic phases were washed with water, brine, and dried over sodiumsulfate, and then evaporated under reduced pressure. The residue waspurified by preparative HPLC using water-acetonitrile as mobile phase togive desired product5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 89, 0.1 g, yield: 25.8%) m/z 497.13 [M+1]+ ¹H NMR (400 MHz,DMSO-d₆) δ 12.26 (s, 1H), 9.06 (dd, J=2.9, 1.1 Hz, 1H), 8.17 (d, J=2.7Hz, 1H), 7.89 (t, J=6.1 Hz, 1H), 7.83 (dd, J=5.1, 1.1 Hz, 1H), 7.80 (s,1H), 7.69 (dd, J=5.1, 3.0 Hz, 1H), 6.98 (s, 2H), 6.33 (s, 1H), 4.55 (d,J=6.1 Hz, 2H) ppm.

Example 125—Preparation of Compound 90

The synthesis of Compound 90 followed General Procedure 6 following:

To a cooled solution (0° C.) of pivalic acid (0.278 g, 2.5 mmol, 1.2 eq)in THF (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI.HCl, 0.477 g, 2.5 mmol, 1.2 eq) andN,N-diisopropylethylamine (DIPEA, 0.32 g, 2.5 mmol, 1.2 eq) undernitrogen. After stirring for 30 minutes, hydroxybenzotriazole (HOBt,0.063 g, 0.41 mmol, 0.2 eq) and5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 23, 0.8 g, 2.1 mmol, 1.0 eq) were added. After completion,(monitored by LC-MS), the reaction mixture was poured into water (20 mL)and extracted with ethyl acetate. The combined organic phases werewashed with water, brine, dried over sodium sulfate and evaporated underreduced pressure. The residue was purified by preparative HPLC usingwater-acetonitrile as mobile phase to give desired product5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)pyridin-2(1H)-one(Compound 90, 0.45 g, yield: 48.3%) m/z 471.46 [M+1]+ ¹H NMR (400 MHz,DMSO-d₆) δ 12.27 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.79 (s, 2H), 6.96(dd, J=13.5, 3.7 Hz, 2H), 6.20 (s, 1H), 4.48 (d, J=6.0 Hz, 2H), 1.47 (s,9H) ppm.

Example 126—Preparation of Compound 91

The synthesis of Compound 91 followed the procedure of General Procedure8 following.

To a solution of Compound 90 at room temperature (0.2 g, 0.41 mmol, 1.0eq) in DMF (12 mL) was added cesium carbonate (0.334 g, 1.02 mmol, 2.5eq) and 4-(chloroacetyl)morpholine (0.101 g, 0.62 mmol, 1.5 eq). Thereaction mixture was stirred for 12 hours. After completion (monitoredby TLC), the reaction mixture was poured into water (30 mL) andextracted with ethyl acetate. The combined organic phases were washedwith water, then brine, dried over sodium sulfate and then evaporatedunder reduced pressure. The residue was purified by columnchromatography using ethyl acetate-hexane as mobile phase to afford thedesired product5-bromo-3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(1H)-one(Compound 91, 0.075 g, yield: 30.6%) m/z 598.40 [M+1]+ ¹H NMR (400 MHz,DMSO-d₆) δ 8.08-8.04 (m, 2H), 7.81 (s, 1H), 6.97 (d, J=3.7 Hz, 1H), 6.93(d, J=3.7 Hz, 1H), 6.17 (s, 1H), 4.91 (s, 2H), 4.47 (d, J=6.0 Hz, 2H),3.66 (s, 2H), 3.59 (s, 2H), 3.54 (s, 2H), 3.45 (s, 2H), 1.48 (s, 9H)ppm.

Example 127—Preparation of Compound 92

The synthesis of Compound 92 followed General Procedure 14 following:

To a stirred solution of3-bromo-6-(5-(((5-chlorothiophene-2-yl)methyl)amino)-1H-pyrazol-3-yl)pyridine-2(1H)-one(Compound 66, 0.120 g, 0.31 mmol, 1.0 eq) in dioxane:water (4:1; 15 mL)was added vinylboronic acid pinacol ester (0.071 g, 0.47 mmol, 1.5 eq),followed by potassium carbonate (K₂CO₃, 0.127 g, 0.93 mmol, 3 eq). Thereaction mixture was degassed for 10 minutes, followed by the additionof 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride(PdCl₂(dppf), 0.0226 g, 0.03 mmol, 0.1 eq). The reaction mixture wasagain degassed for 10 minutes and then heated at 100° C. for 2 hours.After completion (as monitored by LC-MS), the reaction mixture waspoured into water (5 mL) and extracted with ethyl acetate (2×15 mL). Thecombined organic phases were washed with water, brine, dried over sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography using 60-120 mesh size silica gel, eluting with0-20% ethyl acetate in n-hexane as mobile phase to give pure desiredproduct6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-vinylpyridin-2(1H)-one(Compound 92, 0.090 g, yield: 86.9%) m/z 333.4 [M+1]+ ¹H NMR (400 MHz,DMSO) δ 12.29 (s, 1H), 11.12 (s, 1H), 7.63 (s, 1H), 6.95 (s, 2H),6.81-6.59 (m, 2H), 6.37 (d, J=41.2 Hz, 2H), 6.12 (d, J=17.9 Hz, 2H),5.24 (d, J=10.8 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H) ppm.

Example 128—Preparation of Compound 93

The synthesis of Compound 93 followed the procedure of General Procedure6 following:

To a cooled solution (0° C.) of pivalic acid (0.011 g, 0.11 mmol, 1.2eq) in THF (5 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl,0.021 g, 0.11 mmol, 1.2 eq), followed by triethylamine (0.028 g, 0.27mmol, 3.0 eq) under nitrogen. After stirring for 30 minutes,hydroxybenzotriazole (HOBt, 0.0024 g, 0.018 mmol, 0.2 eq) and6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-vinylpyridin-2(1H)-one(Compound 92) were added. The reaction was monitored by LC-MS. Aftercompletion, the reaction mixture was poured into water (10 mL) andextracted with ethyl acetate. The combined organic phases were washedwith water, brine, dried over sodium sulphate and evaporated underreduced pressure. The residue was purified by preparative HPLC usingwater-acetonitrile as mobile phase to give the desired product6-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1-pivaloyl-1H-pyrazol-3-yl)-3-vinylpyridin-2(1H)-one(Compound 93, 0.005 g, yield—13.3%) m/z 416.51 [M]+ ¹H NMR (400 MHz,DMSO) δ 12.56 (s, 1H), 8.19 (d, J=7.4 Hz, 1H), 8.01 (d, J=6.1 Hz, 1H),7.52 (d, J=7.7 Hz, 1H), 7.16-6.82 (m, 4H), 6.53 (s, 1H), 6.27 (s, 1H),4.46 (d, J=6.1 Hz, 2H), 1.46 (s, 9H) ppm.

Exemplary thrombin- and kallikrein-inhibiting compounds in accordancewith the present disclosure are prepared according to any of Examples1-128 and are listed in Table B (Appendix A).

The various methods and techniques described above provide a number ofways to carry out the application. Of course, it is to be understoodthat not necessarily all objectives or advantages described can beachieved in accordance with any particular embodiment described herein.Thus, for example, those skilled in the art will recognize that themethods can be performed in a manner that achieves or optimizes oneadvantage or group of advantages as taught herein without necessarilyachieving other objectives or advantages as taught or suggested herein.A variety of alternatives are mentioned herein. It is to be understoodthat some preferred embodiments specifically include one, another, orseveral features, while others specifically exclude one, another, orseveral features, while still others mitigate a particular feature byinclusion of one, another, or several advantageous features.

Furthermore, the skilled artisan will recognize the applicability ofvarious features from different embodiments. Similarly, the variouselements, features and steps discussed above, as well as other knownequivalents for each such element, feature or step, can be employed invarious combinations by one of ordinary skill in this art to performmethods in accordance with the principles described herein. Among thevarious elements, features, and steps some will be specifically includedand others specifically excluded in diverse embodiments.

Although the application has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the embodiments of the application extend beyond thespecifically disclosed embodiments to other alternative embodimentsand/or uses and modifications and equivalents thereof.

In some embodiments, the numbers expressing quantities of ingredients,properties such as molecular weight, reaction conditions, and so forth,used to describe and claim certain embodiments of the application are tobe understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth inthe written description and attached claims are approximations that canvary depending upon the desired properties sought to be obtained by aparticular embodiment. In some embodiments, the numerical parametersshould be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof some embodiments of the application are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspracticable.

In some embodiments, the terms “a” and “an” and “the” and similarreferences used in the context of describing a particular embodiment ofthe application (especially in the context of certain of the followingclaims) can be construed to cover both the singular and the plural. Therecitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (for example, “such as”) provided withrespect to certain embodiments herein is intended merely to betterilluminate the application and does not pose a limitation on the scopeof the application otherwise claimed. No language in the specificationshould be construed as indicating any non-claimed element essential tothe practice of the application.

Preferred embodiments of this application are described herein,including the best mode known to the inventors for carrying out theapplication. Variations on those preferred embodiments will becomeapparent to those of ordinary skill in the art upon reading theforegoing description. It is contemplated that skilled artisans canemploy such variations as appropriate, and the application can bepracticed otherwise than specifically described herein. Accordingly,many embodiments of this application include all modifications andequivalents of the subject matter recited in the claims appended heretoas permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof isencompassed by the application unless otherwise indicated herein orotherwise clearly contradicted by context.

All patents, patent applications, publications of patent applications,and other material, such as articles, books, specifications,publications, documents, things, and/or the like, referenced herein arehereby incorporated herein by this reference in their entirety for allpurposes, excepting any prosecution file history associated with same,any of same that is inconsistent with or in conflict with the presentdocument, or any of same that may have a limiting affect as to thebroadest scope of the claims now or later associated with the presentdocument. By way of example, should there be any inconsistency orconflict between the description, definition, and/or the use of a termassociated with any of the incorporated material and that associatedwith the present document, the description, definition, and/or the useof the term in the present document shall prevail.

In closing, it is to be understood that the embodiments of theapplication disclosed herein are illustrative of the principles of theembodiments of the application. Other modifications that can be employedcan be within the scope of the application. Thus, by way of example, butnot of limitation, alternative configurations of the embodiments of theapplication can be utilized in accordance with the teachings herein.Accordingly, embodiments of the present application are not limited tothat precisely as shown and described.

APPENDIX A Table B1-(2-aminobenzoyl)-3-[1-benzyl-5-(morpholin-4-yl)-6-oxo-1,6-dihydropyridin-2-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-4-carbonitrile1-(2-carboxy-2-oxoethyl)-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylicacid1-benzoyl-3-(1-benzyl-2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-4-carbonitrile1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-(morpholin-4-ylmethyl)-2-oxo-6-(2-phenylethynyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-4-carbonitrile 1-benzyl-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1,2-dihydropyridin-2-one1-benzyl-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-3-ethenyl-1,2-dihydropyridin-2-one1-benzyl-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-4-hydroxy-1,2-dihydropyridin-2-one2-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carbonitrile2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carboxylic acid2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)ethyl]-6-oxo-1,6-dihydropyridine-3-carbonitrile2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-5-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile2-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile2-[3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetic acid2-[3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-hydroxy-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-2-oxo-4-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-phenyl-1,2-dihydropyridin-1-yl]acetaldehyde2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-3-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-fluoro-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-5-methoxy-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridine-2-carbonyl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-6-(prop-2-enoyl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-hydroxy-2-oxo-1,2-dihydropyridin-1-yl]aceticacid2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(methoxycarbonyl)-2-oxo-1,2-dihydropyridin-1-yl]acetic acid2-[4-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetic acid2-[5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-3-(pyridin-3-yl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1H-pyrazol-3-yl)-6-ethenyl-2-oxo-1,2-dihydropyridin-1-yl]acetic acid2-[5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-6-(pyridin-3-yl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-6-(2-phenylethynyl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[5-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-4-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]aceticacid2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-ethenyl-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]acetaldehyde2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetaldehyde2-{3-[1-(3-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-5-chloro-2-oxo-1,2-dihydropyridin-1-yl}acetic acid2-{4-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazol-3-yl]-3-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl}acetic acid2-{6-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-2-oxo-3-phenyl-1,2-dihydropyridin-1-yl}acetaldehyde2-{6-[1-(4-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-2-oxo-5-(2-phenylethynyl)-1,2-dihydropyridin-1-yl}aceticacid3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-5-methoxy-1-[2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-6-(2-phenylethynyl)-1-[2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-6-oxo-1-[2-(thiophen-2-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile3-(3-{2-chloro-6-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridin-3-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzamide3-(3-{3-chloro-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridin-2-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzamide3-(3-{5-bromo-6-oxo-1-[2-(1,2-thiazol-4-yl)ethyl]-1,6-dihydropyridin-2-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzamide3-(3-{6-chloro-2-oxo-1-[2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-4-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-5-methoxy-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-6-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-5-(pyridin-4-yl)-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-4-phenyl-1-(1,3-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-(1,3-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-5-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-6-(pyridin-2-yl)-1-[2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-5-methoxy-1-(1,3-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(piperidin-1-ylmethyl)-1,2-dihydropyridine-4-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-5-hydroxy-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-fluoro-1-(1,3-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-5-ylmethyl)-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-6-(prop-2-enoyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-4-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-4-(prop-2-enoyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-4-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-5-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-5-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-6-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-6-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-4-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-5-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-5-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-6-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-4-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-5-(prop-2-enoyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridine-4-carboxylic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholine-4-carbonyl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholine-4-carbonyl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholine-4-carbonyl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-4-carboxamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-6-oxo-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,6-dihydropyridine-2-carboxamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-2-ylmethyl)-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-methyl-6-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one 3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(pyrazin-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-(1,2-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-4-methoxy-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-(1,3-oxazol-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-4-(pyridin-2-yl)-1-(1,3-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyrazin-2-ylmethyl)-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)ethyl]-5-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-4-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-4-(pyridin-3-yl)-1-[2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-5-(pyridin-2-yl)-1-[2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-6-methoxy-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-(2-phenylethyl)-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-6-fluoro-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-6-hydroxy-1-[2-(1,3-oxazol-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-ethenyl-1-[2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-5-methoxy-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-4-methoxy-1H-pyrazol-3-yl)-6-hydroxy-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-(furan-2-ylmethyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-methyl-5-(morpholin-4-yl)-6-oxo-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-fluoro-6-oxo-1-(pyridin-4-ylmethyl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-oxo-1-(2-oxo-2-phenylethyl)-3-(pyridin-4-yl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-oxo-5-(2-phenylethynyl)-1-[2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(dimethylamino)-1-(1,3-oxazol-5-ylmethyl)-6-oxo-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(methoxycarbonyl)-1-[2-(1,2-oxazol-3-yl)ethyl]-6-oxo-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(morpholin-4-yl)-6-oxo-1-(1,3-thiazol-4-ylmethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-hydroxy-2-oxo-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-3-yl]-4-methoxy-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(dimethylamino)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(dimethylamino)-1-[2-(furan-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(morpholin-4-yl)-1-[2-(1,2-oxazol-3-yl)ethyl]-6-oxo-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(morpholin-4-yl)-6-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-fluoro-2-oxo-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-(morpholin-4-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-(morpholin-4-yl)-2-oxo-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-oxo-1-(2-oxoethyl)-4-(pyridin-4-yl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{2-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{2-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{2-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-5-phenyl-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{3-hydroxy-2-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-cyano-6-oxo-1-[2-(piperidin-1-yl)ethyl]-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-ethenyl-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-ethenyl-6-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-hydroxy-6-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{5-cyano-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-ethenyl-1-[2-(1,3-oxazol-4-yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-hydroxy-2-oxo-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-phenyl-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-oxo-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-3-phenyl-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzoicacid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-oxo-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-4-(pyridin-3-yl)-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[5-cyano-2-oxo-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[6-methoxy-2-oxo-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-{1-[(4-methylpiperazin-1-yl)methyl]-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-ethenyl-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-4-ylmethyl)-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-5-ylmethyl)-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-(morpholin-4-ylmethyl)-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-4-methoxy-1-(1,3-oxazol-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-6-fluoro-1-(pyridazin-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-4-(pyridin-3-yl)-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-(1,2-oxazol-5-ylmethyl)-5-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-6-(pyridin-4-yl)-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-(morpholin-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-methyl-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[(4-methylpiperazin-1-yl)methyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(2-phenylethynyl)-1-(pyridazin-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-(1,2-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-5-methoxy-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-3-[5-(methoxycarbonyl)-2-oxo-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-3-[6-oxo-5-(2-phenylethynyl)-1-(pyridin-4-ylmethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzamide3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-6-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carbonitrile3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-4-hydroxy-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-4-phenyl-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-oxo-2-(pyridin-2-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one3-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-4-(dimethylamino)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-4-bromo-1-(1,3-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile3-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-pyrazol-3-yl]-5-(morpholin-4-yl)-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-5-hydroxy-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-pyrazol-3-yl]-1-[(4-methylpiperazin-1-yl)methyl]-6-oxo-1,6-dihydropyridine-2-carbonitrile3-[3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-4-phenyl-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-5-(2-phenylethynyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-6-(pyridin-3-yl)-1,2-dihydropyridin-1-yl]propanoicacid3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-6-fluoro-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-5-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]propanoicacid3-[3-chloro-1-(1,2-oxazol-3-ylmethyl)-2-oxo-1,2-dihydropyridin-4-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazole-4-carbonitrile3-[4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-3-phenyl-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[4-bromo-1-(furan-3-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazole-4-carbonitrile3-[4-chloro-2-oxo-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-3-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazole-4-carbonitrile3-[5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-3-cyano-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-3-(pyridine-3-carbonyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(2-methoxy-2-oxoacetyl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholine-4-carbonyl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-6-(pyridin-4-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-hydroxy-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid3-[5-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-3-phenyl-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-4-phenyl-1,2-dihydropyridin-1-yl]-2-oxopropanoicacid3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(methoxycarbonyl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-3-(pyridin-3-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoic acid3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoicacid3-[6-chloro-2-oxo-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-3-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazole-4-carbonitrile3-benzoyl-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-benzoyl-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one3-benzoyl-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)ethyl]-1,2-dihydropyridin-2-one 3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-2-one3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one3-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-4-methoxy-1H-pyrazol-3-yl)-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-2-one3-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one 3-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one 3-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-2-one3-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridin-2-one3-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one3-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one3-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one3-{3-[1-(2-carboxy-2-oxoethyl)-6-cyano-2-oxo-1,2-dihydropyridin-4-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl}benzoic acid3-{3-[4-bromo-6-oxo-1-(1,3-thiazol-5-ylmethyl)-1,6-dihydropyridin-3-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1H-pyrazole-1-carbonyl}benzoicacid3-{3-[4-bromo-6-oxo-1-(pyridin-4-ylmethyl)-1,6-dihydropyridin-2-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazole-1-carbonyl}benzoic acid3-{3-[5-bromo-6-oxo-1-(1,2-thiazol-3-ylmethyl)-1,6-dihydropyridin-3-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl}benzoic acid4-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-6-hydroxy-1-[2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile4-(3-{2-bromo-1-[2-(1,3-oxazol-5-yl)ethyl]-6-oxo-1,6-dihydropyridin-3-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzoicacid4-(3-{3-bromo-6-oxo-1-[2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridin-2-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzoicacid4-(3-{5-chloro-6-oxo-1-[2-(1,2-thiazol-3-yl)ethyl]-1,6-dihydropyridin-3-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzoicacid4-(3-{5-chloro-6-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,6-dihydropyridin-3-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzamide4-(3-{6-chloro-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-4-yl}-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-5-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-3-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-(2-oxoethyl)-1,6-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-6-methoxy-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-3-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-5-(pyridin-2-yl)-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-6-(morpholin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)ethyl]-6-oxo-1,6-dihydropyridine-2-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-(2-phenylethynyl)-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-5-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[(4-methylpiperazin-1-yl)methyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(pyridin-2-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(pyridazin-4-ylmethyl)-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-ethenyl-1-(furan-2-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carboxylic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-3-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-3-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-5-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-6-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-3-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-6-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-5-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-3-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-3-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-6-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-3-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-5-(prop-2-enoyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-5-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-3-(prop-2-enoyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholine-4-carbonyl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholine-4-carbonyl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-(furan-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholine-4-carbonyl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-hydroxy-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,6-dihydropyridine-2-carboxylic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridine-3-carboxamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-6-oxo-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,6-dihydropyridine-2-carboxamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-6-oxo-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,6-dihydropyridine-3-carboxamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(pyrazin-2-ylmethyl)-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)ethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-ethyl-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-4-methoxy-1H-pyrazol-3-yl)-5-fluoro-1-(1,3-oxazol-2-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[(4-methylpiperazin-1-yl)methyl]-6-phenyl-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-3-phenyl-1-(pyridazin-4-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-5-hydroxy-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-6-phenyl-1-[2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-(pyridin-3-yl)-1-[2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-hydroxy-1-(1,2-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-(1,2-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-5-methoxy-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-3-fluoro-1-[2-(morpholin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-4-methoxy-1H-pyrazol-3-yl)-5-ethenyl-1-(1,2-oxazol-3-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-4-methoxy-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(1,3-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-(1-ethyl-2-oxo-5-phenyl-1,2-dihydropyridin-4-yl)-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-(dimethylamino)-6-oxo-1-(2-oxo-2-phenylethyl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-oxo-6-(2-phenylethynyl)-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-(dimethylamino)-6-oxo-1-(2-oxoethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-(morpholin-4-yl)-2-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-methoxy-2-oxo-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(morpholin-4-yl)-6-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-hydroxy-6-oxo-1-(piperidin-1-ylmethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(dimethylamino)-1-[2-(1,2-oxazol-5-yl)ethyl]-2-oxo-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(dimethylamino)-2-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(methoxycarbonyl)-1-(1,2-oxazol-3-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-hydroxy-2-oxo-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-oxo-4-(pyridin-3-yl)-1-[2-(pyridin-3-yl)ethyl]-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-oxo-5-(pyridin-3-yl)-1-[2-(1,3-thiazol-4-yl)ethyl]-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{1-[(4-methylpiperazin-1-yl)methyl]-2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-2-oxo-6-phenyl-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-6-oxo-5-(pyridin-3-yl)-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{1-[2-(furan-2-yl)ethyl]-4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{3-cyano-1-[2-(furan-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{3-hydroxy-2-oxo-1-[2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-cyano-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-hydroxy-1-[2-(morpholin-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-hydroxy-6-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{4-methoxy-2-oxo-1-[2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{5-ethenyl-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{5-ethenyl-6-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{5-fluoro-1-[2-(1,3-oxazol-2-yl)ethyl]-6-oxo-1,6-dihydropyridin-2-yl}-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-cyano-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoicacid 4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-methoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridin-4-yl}-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-(pyridin-4-yl)-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{6-oxo-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-5-phenyl-1,6-dihydropyridin-3-yl}-1H-pyrazole-1-carbonyl)benzoicacid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[4-cyano-1-(1,2-oxazol-5-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[5-(morpholin-4-yl)-2-oxo-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[5-hydroxy-2-oxo-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[6-oxo-1-(pyridazin-4-ylmethyl)-3-(pyridin-4-yl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-3-[6-oxo-2-(pyridin-4-yl)-1-(1,3-thiazol-4-ylmethyl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-5-phenyl-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-(1,3-thiazol-4-ylmethyl)-1,6-dihydropyridine-2-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(2-phenylethynyl)-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-(piperidin-1-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-4-ylmethyl)-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-3-(pyridin-3-yl)-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-(piperidin-1-ylmethyl)-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-3-[4-(methoxycarbonyl)-6-oxo-1-(pyrimidin-4-ylmethyl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-3-[6-fluoro-2-oxo-1-(1,3-thiazol-5-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carbonitrile4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-3-(pyridin-2-yl)-1-(1,3-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(furan-2-ylmethyl)-3-hydroxy-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-4-ylmethyl)-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-phenyl-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-6-methoxy-1-(1,3-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-3-[6-(morpholin-4-yl)-1-(1,2-oxazol-3-ylmethyl)-2-oxo-1,2-dihydropyridin-4-yl]-1H-pyrazole-1-carbonyl)benzamide4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-3-[6-oxo-1-(pyridin-3-ylmethyl)-4-(pyridin-4-yl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-1-carbonyl)benzoic acid4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one4-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-(2-oxo-2-phenylethyl)-5-phenyl-1,2-dihydropyridin-2-one4-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-(furan-2-yl)-2-oxoethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-5-(morpholin-4-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-ethenyl-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-(pyridin-3-ylmethyl)-1,6-dihydropyridine-3-carbonitrile4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-pyrazol-3-yl]-1-(pyrazin-2-ylmethyl)-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-pyrazol-3-yl]-5-methoxy-1-(1,3-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one4-[3-(1-benzyl-2-chloro-6-oxo-1,6-dihydropyridin-3-yl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazole-1-carbonyl]benzamide4-[3-(1-benzyl-4-ethenyl-2-oxo-1,2-dihydropyridin-3-yl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl]benzamide4-benzoyl-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-benzoyl-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-benzoyl-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one4-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one4-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one4-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)ethyl]-1,2-dihydropyridin-2-one 4-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one 4-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one4-chloro-5-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one4-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one4-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one4-{3-[1-(2-carboxy-2-oxoethyl)-2-oxo-5-(pyridin-3-yl)-1,2-dihydropyridin-4-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl}benzoicacid4-{3-[3-chloro-6-oxo-1-(pyrazin-2-ylmethyl)-1,6-dihydropyridin-2-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl}benzoic acid4-{3-[4-chloro-1-(1,2-oxazol-3-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazole-1-carbonyl}benzamide4-{3-[4-chloro-6-oxo-1-(pyrimidin-4-ylmethyl)-1,6-dihydropyridin-2-yl]-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1H-pyrazole-1-carbonyl}benzamide5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-4-phenyl-1,2-dihydropyridin-2-one5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-3-chloro-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-4-methoxy-1-[2-(1,3-oxazol-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1H-pyrazol-3-yl)-2-oxo-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridine-4-carbonitrile5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-pyrazol-3-yl)-1-[(4-methylpiperazin-1-yl)methyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one 5-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazol-3-yl)-1-[(4-methylpiperazin-1-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one 5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-3-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-4-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-(furan-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-4-(pyridin-4-yl)-1-[2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-6-(2-phenylethynyl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-phenyl-1-[2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(piperidin-1-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-ethenyl-1-(1,2-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-3-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-3-phenyl-1-[2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-(pyrimidin-2-ylmethyl)-1,6-dihydropyridine-2-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-6-ethenyl-1-(1,2-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-(1,2-thiazol-3-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-(morpholin-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-4-ethenyl-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-4-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-4-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-3-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-6-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-6-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-4-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-4-(morpholine-4-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-6-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-3-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-4-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-6-(prop-2-enoyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-4-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-4-(prop-2-enoyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-3-(prop-2-enoyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-3-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-6-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-6-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridine-4-carboxylicacid5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-4-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridine-3-carboxylic acid5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholine-4-carbonyl)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-hydroxy-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,6-dihydropyridine-2-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,6-dihydropyridine-3-carboxylic acid5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,6-dihydropyridine-2-carboxylic acid5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridine-4-carboxamide5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridine-3-carboxamide5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-6-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,6-dihydropyridine-2-carboxamide5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one 5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)ethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one 5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-4-methoxy-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(pyridin-3-yl)-1-[2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-5-ylmethyl)-3-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-3-(2-phenylethynyl)-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-(1,3-oxazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-6-ethenyl-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-4-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-(pyridazin-4-ylmethyl)-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)ethyl]-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-4-phenyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-(1,2-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-(morpholin-4-ylmethyl)-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridine-4-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-ethyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-(1,3-oxazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-6-(pyridin-3-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-3-methoxy-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-ethenyl-1-[2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-fluoro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-hydroxy-1-methyl-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-6-hydroxy-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-6-methoxy-1-[2-(morpholin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-6-oxo-1-(2-phenylethyl)-1,6-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-3-methoxy-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-4-methoxy-1H-pyrazol-3-yl)-4-fluoro-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-6-phenyl-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-3-(pyridin-2-yl)-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-4-(2-phenylethynyl)-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-(pyridin-2-yl)-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-4-methoxy-1-(pyridin-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-(pyridazin-4-ylmethyl)-1,2-dihydropyridin-2-one 5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-2-oxo-1-(pyridazin-4-ylmethyl)-1,2-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-3-hydroxy-1-(1,2-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-6-methoxy-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-4-ethenyl-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-6-oxo-1-(1,3-thiazol-2-ylmethyl)-1,6-dihydropyridine-2-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-6-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carbonitrile5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-6-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(morpholin-4-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-fluoro-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-methoxy-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-3-bromo-1-[2-(1,3-oxazol-2-yl)ethyl]-1,2-dihydropyridin-2-one5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-4-(dimethylamino)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-4-(pyridin-2-yl)-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-chloro-1-methyl-1,2-dihydropyridin-2-one5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridine-3-carbonitrile5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazol-3-yl]-6-(2-phenylethynyl)-1-(1,3-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one5-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-3-ethenyl-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one5-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-hydroxy-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1H-pyrazol-3-yl]-6-(morpholin-4-yl)-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridin-2-one5-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazol-3-yl]-4-(pyridin-2-yl)-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one 5-benzoyl-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-benzoyl-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-benzoyl-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one5-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one5-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)ethyl]-1,2-dihydropyridin-2-one5-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one5-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one5-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one 5-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one5-bromo-6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one 5-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-4-methoxy-1H-pyrazol-3-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one5-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-chloro-3-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one5-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridin-2-one5-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one5-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one5-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(furan-2-ylmethyl)-1,2-dihydropyridin-2-one5-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one5-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one5-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(2-phenylethyl)-1,2-dihydropyridin-2-one5-chloro-6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-methyl-1,2-dihydropyridin-2-one5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-3-[6-oxo-5-(pyridin-2-yl)-1-(1,2-thiazol-5-ylmethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-3-[6-oxo-4-phenyl-1-(piperidin-1-ylmethyl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-3-[1-(furan-2-ylmethyl)-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-3-[4-methoxy-6-oxo-1-(thiophen-3-ylmethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-3-[6-oxo-1-(pyrazin-2-ylmethyl)-5-(pyridin-3-yl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile 5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-3-[2-oxo-5-(pyridin-4-yl)-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-3-[6-oxo-4-phenyl-1-(pyridazin-4-ylmethyl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-3-[1-(furan-3-ylmethyl)-6-oxo-3-(pyridin-3-yl)-1,6-dihydropyridin-2-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-3-[2-oxo-3-phenyl-1-(1,3-thiazol-4-ylmethyl)-1,2-dihydropyridin-4-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-3-[5-hydroxy-2-oxo-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-3-[6-oxo-1-(piperidin-1-ylmethyl)-2-(pyridin-3-yl)-1,6-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-3-[4-(morpholin-4-yl)-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-3-yl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-(1,2-oxazol-4-ylmethyl)-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl]-1-(1,3-oxazole-5-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-(1,3-oxazol-5-ylmethyl)-2-oxo-5-(pyridin-2-yl)-1,2-dihydropyridin-4-yl]-1-(1,3-thiazole-2-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[1-methyl-2-oxo-6-(pyridin-3-yl)-1,2-dihydropyridin-4-yl]-1-(1,2-oxazole-4-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-fluoro-1-(1,3-oxazol-4-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl]-1-(thiophene-3-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-hydroxy-1-(1,2-oxazol-3-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl]-1-(1,2-oxazole-5-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-oxo-5-(pyridin-3-yl)-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-3-yl]-1-(thiophene-2-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[2-oxo-5-(pyridin-4-yl)-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-4-yl]-1-(1,2-thiazole-3-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-(dimethylamino)-2-oxo-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-4-yl]-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-ethenyl-1-(1,2-oxazol-4-ylmethyl)-6-oxo-1,6-dihydropyridin-2-yl]-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-fluoro-6-oxo-1-(pyridin-4-ylmethyl)-1,6-dihydropyridin-2-yl]-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-hydroxy-6-oxo-1-(pyrimidin-4-ylmethyl)-1,6-dihydropyridin-2-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[3-methoxy-1-(1,3-oxazol-2-ylmethyl)-2-oxo-1,2-dihydropyridin-4-yl]-1-(thiophene-3-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[4-(dimethylamino)-1-[(4-methylpiperazin-1-yl)methyl]-6-oxo-1,6-dihydropyridin-2-yl]-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-(dimethylamino)-6-oxo-1-(pyridin-3-ylmethyl)-1,6-dihydropyridin-3-yl]-1-(furan-2-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-ethenyl-1-(furan-2-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl]-1-(1,3-thiazole-4-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-ethenyl-2-oxo-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-3-yl]-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[5-hydroxy-6-oxo-1-(1,3-thiazol-2-ylmethyl)-1,6-dihydropyridin-2-yl]-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-(dimethylamino)-1-(furan-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl]-1-(1,3-oxazole-4-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-(dimethylamino)-2-oxo-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-4-yl]-1-(2-fluorobenzoyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-ethenyl-2-oxo-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-4-yl]-1-(1,2-thiazole-5-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-[6-oxo-5-(2-phenylethynyl)-1-(1,2-thiazol-4-ylmethyl)-1,6-dihydropyridin-3-yl]-1-(thiophene-3-carbonyl)-1H-pyrazole-4-carbonitrile5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-{5-fluoro-1-[(4-methylpiperazin-1-yl)methyl]-2-oxo-1,2-dihydropyridin-3-yl}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazole-4-carbonitrile6-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile6-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-4-bromo-1-(1,2-oxazol-3-ylmethyl)-1,2-dihydropyridin-2-one6-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-5-hydroxy-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one6-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazol-3-yl)-3-ethenyl-1-(pyrimidin-4-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-5-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-4-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-4-ylmethyl)-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(morpholin-4-ylmethyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)ethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-5-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-(furan-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-(1,3-thiazol-4-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(1,3-oxazol-5-ylmethyl)-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-5-(2-phenylethynyl)-1-[2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-3-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-5-phenyl-1-[2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-4-methoxy-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-3-ylmethyl)-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-oxo-2-phenylethyl)-4-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carboxylic acid6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-4-(prop-2-enoyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-5-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-3-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-3-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-5-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-4-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-3-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-5-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-5-(pyridine-3-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-4-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-3-(pyridine-4-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-3-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-5-(prop-2-enoyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-3-(prop-2-enoyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-4-(pyridine-2-carbonyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-4-yl)ethyl]-5-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-3-yl)ethyl]-4-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridine-4-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridine-3-carboxylic acid6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(morpholine-4-carbonyl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholine-4-carbonyl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-hydroxy-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholine-4-carbonyl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-hydroxy-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-N,N-dimethyl-2-oxo-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridine-4-carboxamide6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-4-fluoro-1H-pyrazol-3-yl)-5-(pyridin-2-yl)-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-(2-phenylethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-4-ethenyl-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-4-methoxy-1H-pyrazol-3-yl)-5-(2-phenylethynyl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(pyrazin-2-ylmethyl)-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-(thiophen-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(2-phenylethynyl)-1-[2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-ethenyl-1-[2-(1,2-oxazol-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(pyrazin-2-yl)ethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-3-hydroxy-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-[2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-5-ethenyl-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridine-3-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-4-(dimethylamino)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-1-(1,3-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-5-(pyridin-2-yl)-1-[2-(thiophen-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-4-methoxy-1H-pyrazol-3-yl)-1-(pyridazin-4-ylmethyl)-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-4-methoxy-1H-pyrazol-3-yl)-4-hydroxy-1-(1,2-oxazol-5-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-4-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-5-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-(furan-2-ylmethyl)-5-methoxy-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-(1,3-oxazol-2-ylmethyl)-3-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-3-hydroxy-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-3-phenyl-1-[2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-4-fluoro-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-(1,3-oxazol-2-ylmethyl)-4-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-3-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-5-methoxy-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-4-methoxy-1H-pyrazol-3-yl)-3-fluoro-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-(1,3-oxazol-2-ylmethyl)-5-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-(pyridin-2-yl)-1-[2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-4-fluoro-1-[2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-5-fluoro-1-(1,2-oxazol-3-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridine-3-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-4-fluoro-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-(morpholin-4-ylmethyl)-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(morpholin-4-ylmethyl)-5-phenyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-3-methoxy-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-1-(furan-3-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-4-ethenyl-1-methyl-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-4-(2-phenylethynyl)-1-(pyrazin-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(thiophene-2-carbonyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-(1,2-oxazol-4-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(furan-3-ylmethyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-5-methoxy-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-4-(pyridin-2-yl)-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-3-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-5-yl)-2-oxoethyl]-4-(pyridin-2-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-5-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-4-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-4-(2-phenylethynyl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-3-(pyridin-4-yl)-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-fluoro-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-methoxy-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-fluoro-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-4-methoxy-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-(morpholin-4-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-fluoro-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-methoxy-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-4-(pyridin-3-yl)-1,2-dihydropyridin-2-one6-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-3-(dimethylamino)-1-[2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one6-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-(1,3-oxazol-4-ylmethyl)-2-oxo-1,2-dihydropyridine-4-carbonitrile6-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-3-(morpholin-4-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-5-hydroxy-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-benzoyl-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-benzoyl-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-(morpholin-4-ylmethyl)-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-2-one6-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-4-methoxy-1H-pyrazol-3-yl)-1-(1,3-oxazol-2-ylmethyl)-1,2-dihydropyridin-2-one6-bromo-4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-2-one6-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(thiophen-2-yl)ethyl]-1,2-dihydropyridin-2-one6-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-thiazol-5-ylmethyl)-1,2-dihydropyridin-2-one 6-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(pyrimidin-5-ylmethyl)-1,2-dihydropyridin-2-one6-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-3-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyrimidin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridin-2-one6-chloro-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridin-2-one6-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-1,2-dihydropyridin-2-one6-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-2-one6-chloro-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridin-2-one methyl1-benzyl-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-2-carboxylatemethyl1-benzyl-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-(piperidin-1-ylmethyl)-1,6-dihydropyridine-3-carboxylate methyl 2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-5-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl2-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl2-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-(furan-2-yl)ethyl]-6-oxo-1,6-dihydropyridine-3-carboxylatemethyl2-[1-(4-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl2-[2-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrimidin-4-yl)ethyl]-1,6-dihydropyridin-3-yl]-2-oxoacetate methyl2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,2-oxazol-3-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridin-2-yl]-2-oxoacetate methyl2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridin-4-yl]-2-oxoacetate methyl2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-6-methoxy-2-oxo-1,2-dihydropyridin-1-yl]acetate methyl2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-4-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]acetate methyl2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridin-3-yl]-2-oxoacetate methyl2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridin-3-yl]-2-oxoacetate methyl2-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,6-dihydropyridin-2-yl]-2-oxoacetate methyl2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-3-(pyridin-3-yl)-1,2-dihydropyridin-1-yl]acetate methyl2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-4-cyano-2-oxo-1,2-dihydropyridin-1-yl]acetatemethyl 2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridin-3-yl]-2-oxoacetate methyl2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,6-dihydropyridin-2-yl]-2-oxoacetate methyl2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,6-dihydropyridin-3-yl]-2-oxoacetate methyl2-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(thiophene-3-carbonyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]acetate methyl2-[5-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetatemethyl 2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridin-3-yl]-2-oxoacetate methyl2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1,2-dihydropyridin-4-yl]-2-oxoacetate methyl2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-3-phenyl-1,2-dihydropyridin-1-yl]acetate methyl2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-2-oxo-4-(pyridin-4-yl)-1,2-dihydropyridin-1-yl]acetate methyl2-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-5-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]acetate methyl3-(1-benzoyl-5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1H-pyrazol-3-yl)-1-(furan-2-ylmethyl)-6-oxo-1,6-dihydropyridine-2-carboxylatemethyl 3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridazin-4-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-2-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-5-ylmethyl)-6-oxo-1,6-dihydropyridine-2-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-4-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-(pyrimidin-5-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(morpholin-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-fluoro-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridine-4-carboxylate methyl3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl3-[1-(4-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-4-(3-phenylprop-2-ynoyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-phenyl-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-4-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-3-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-cyano-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-5-ethenyl-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-3-(morpholin-4-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-2-oxo-3-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]propanoate methyl3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-hydroxy-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridine-4-carbonyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-6-fluoro-2-oxo-1,2-dihydropyridin-1-yl]propanoate methyl3-[4-bromo-3-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-methoxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[4-bromo-5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-3-(dimethylamino)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-3-fluoro-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoatemethyl 3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-3-(2-phenylethynyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-4-phenyl-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[2-(trifluoromethyl)benzoyl]-1H-pyrazol-3-yl)-3-methoxy-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-2-oxo-4-(pyridin-2-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[4-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-2-oxo-5-(2-phenylethynyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-3-(2-phenylethynyl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-[6-benzoyl-4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2-oxopropanoate methyl3-{3-[1-(3-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-5-chloro-2-oxo-1,2-dihydropyridin-1-yl}-2-oxopropanoate methyl3-{4-[1-(3-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-5-methoxy-2-oxo-1,2-dihydropyridin-1-yl}propanoate methyl3-{5-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-2-oxo-6-(2-phenylethynyl)-1,2-dihydropyridin-1-yl}propanoate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-(pyridin-2-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-1-(3-methoxy-2,3-dioxopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-2-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-5-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-(pyrazin-2-ylmethyl)-1,6-dihydropyridine-2-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(1,2-thiazol-3-ylmethyl)-1,2-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl4-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl4-[1-(2-aminobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-(1,2-oxazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl4-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl4-[1-(3-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-6-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl](methyl)amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyridine-2-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-4-carbonyl)-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)-2-oxoethyl]-2-oxo-1,2-dihydropyridine-4-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-1-[2-(furan-3-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-4-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,6-dihydropyridine-2-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-6-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,6-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-fluorobenzoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2-methoxybenzoyl)-1H-pyrazol-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrazin-2-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,2-thiazol-5-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl 5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-[3-(hydroxymethyl)benzoyl]-1H-pyrazol-3-yl)-1-[2-(1,3-oxazol-4-yl)ethyl]-6-oxo-1,6-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-6-oxo-1-(1,3-thiazol-5-ylmethyl)-1,6-dihydropyridine-2-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl5-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl5-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-(3-methoxy-2,3-dioxopropyl)-6-oxo-1,6-dihydropyridine-2-carboxylate methyl5-[1-(4-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-1-[2-(furan-3-yl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,2-thiazole-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(1,3-thiazol-5-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-oxazole-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(pyrimidin-2-ylmethyl)-1,2-dihydropyridine-4-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(1,3-thiazole-5-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-4-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(thiophen-3-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)-1,2-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-cyano-1-(furan-2-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydropyridine-4-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-4-methoxy-1-(1,2-oxazole-5-carbonyl)-1H-pyrazol-3-yl)-1-(1,2-oxazol-4-ylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridine-3-carboxylate methyl6-(5-{[(5-chlorothiophen-2-yl)methyl]sulfanyl}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1-[2-oxo-2-(pyrimidin-5-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl6-[1-(2-chlorobenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-2-oxo-1-[2-oxo-2-(1,2-thiazol-3-yl)ethyl]-1,2-dihydropyridine-4-carboxylate methyl6-[1-(3-carbamoylbenzoyl)-5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl]-2-oxo-1-[2-oxo-2-(pyridin-2-yl)ethyl]-1,2-dihydropyridine-3-carboxylate

1. A compound comprising a substituted or unsubstituted pyridone ringattached to a substituted or unsubstituted pyrazole ring with structureof Formula (I):

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof;wherein L¹ is a bond, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, —S—, —O—, or —NR⁶—; L² and L⁴ areindependently a bond, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, —S—, —SO—, or —SO₂—; L³ and L⁵ areindependently a bond, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, or —O—; R¹ is hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl; R² and R⁴ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl; R³ and R⁵ areindependently hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; and R⁶ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; providedthat if the compound has a structure according to Formula (IIa), asfollows, either L³ is not a bond or R³ is not hydrogen:


2. The compound according to claim 1, with structure of Formula (IIa),Formula (IIIa), Formula (IVa), or Formula (Va):


3. The compound according to claim 2, wherein L² is a bond, and R² ishydrogen.
 4. The compound according to any of Formula (IIIa), Formula(IVa), or Formula (Va) as set forth in claim 2, wherein L³ is a bond,and R³ is hydrogen.
 5. The compound according to claim 2, wherein L⁴ isa bond and R⁴ is hydrogen.
 6. The compound according to claim 2, whereinL⁵ is a bond, and R⁵ is hydrogen.
 7. The compound according to claim 2,wherein L² is —C(O)—, and R² is substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstitutedheterocycloalkenyl, substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl.
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. (canceled)12. The compound according to claim 2, wherein L¹ is bond, —S—, —O—,—NR⁶—, substituted or unsubstituted alkylene, or substituted orunsubstituted heteroalkylene, and R¹ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, substituted or unsubstituted heteroaryl,or substituted or unsubstituted heterocycloalkyl.
 13. (canceled)
 14. Thecompound according to claim 2, wherein L⁴ is a bond or substituted orunsubstituted alkylene, and R⁴ is substituted or unsubstituted aryl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl.
 15. (canceled)
 16. The compound according toclaim 2, wherein L⁴ is substituted or unsubstituted alkylene, and R⁴ issubstituted or unsubstituted heterocycloalkyl, or wherein L⁴ is a bond,and R⁴ is substituted or unsubstituted alkyl or substituted orunsubstituted heteroalkyl.
 17. (canceled)
 18. (canceled)
 19. Thecompound according to claim 2, wherein L³ is bond, and R³ is halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.
 20. (canceled)
 21. (canceled)
 22. The compoundaccording to claim 1, wherein L⁵ is bond, and R⁵ is hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.
 23. The compound according to claim 1, as setforth in Table A.
 24. A pharmaceutical composition comprising a compoundaccording to claim 1, and a pharmaceutically acceptable excipient.
 25. Amethod for treating a disease or disorder in a subject, comprisingadministering a compound according to claim 1, or a pharmaceuticalcomposition comprising a compound according to claim 1, to a subject inneed thereof in an amount effective to treat or prevent said disease ordisorder.
 26. The method according to claim 25, wherein said disease ordisorder is a thrombotic disorder, a kallikrein-related disorder,fibrosis, Alzheimer's Disease, multiple sclerosis, pain, or cancer. 27.The method according to claim 26, wherein said thrombotic disorder isacute coronary syndrome, venous thromboembolism, arterialthromboembolism, cardiogenic thromboembolism, disseminated intravascularcoagulation, or a blood clot thrombus, or wherein saidkallikrein-related disorder is a thrombotic disease, a fibrinolyticdisease, a type of cancer, an inflammatory condition, a dermatologicalcondition, or an ophthalmic disease.
 28. The method according to claim26, wherein said compound acts by inhibiting thrombin, or wherein saidcompound acts by inhibiting plasma kallikrein.
 29. (canceled) 30.(canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. (canceled)